CA2867494A1

CA2867494A1 - Conformationally constrained, fully synthetic macrocyclic compounds

Info

Publication number: CA2867494A1
Application number: CA2867494A
Authority: CA
Inventors: Daniel Obrecht; Philipp Ermert; Said Oumouch; Arnaud Piettre; Jean-Francois Gosalbes; Marc Thommen
Original assignee: Polyphor AG
Current assignee: Spexis AG
Priority date: 2012-03-17
Filing date: 2013-03-15
Publication date: 2013-09-26
Anticipated expiration: 2033-03-15
Also published as: HK1206032A1; EP2836485A1; EP2836485B1; WO2013139697A1; JP2015509970A; SG11201405628YA; US10017481B2; DK2836485T3; AU2013234499A1; US20150051183A1; NZ630901A; AU2013234499B2; MX361923B; CN104284891A; JP6111276B2; CN104284891B; MX2014011078A; IL234595A; CA2867494C

Abstract

The conformationally restricted, spatially defined macrocyclic ring system of formula (I) is constituted by three distinct molecular parts: Template A, conformation Modulator B and Bridge C. Macrocycles described by this ring system I are readily manufactured by parallel synthesis or combinatorial chemistry in solution or on solid phase. They are designed to interact with a variety of specific biological target classes, examples being agonistic or antagonistic activity on G-protein coupled receptors (GPCRs), inhibitory activity on enzymes or antimicrobial activity. In particular, these macrocycles show inhibitory activity on endothelin converting enzyme of subtype 1 (ECE-1 ) and/or the cysteine protease cathepsin S (CatS), and/or act as antagonists of the oxytocin (OT) receptor, thyrotropin-releasing hormone (TRH) receptor and/or leukotriene B4 (LTB4) receptor, and/or as agonists of the bombesin 3 (BB3) receptor, and/or show antimicrobial activity against at least one bacterial strain. Thus they are showing great potential as medicaments for a variety of diseases.

Description

DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

NOTE : Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME

NOTE: For additional volumes, please contact the Canadian Patent Office NOM DU FICHIER / FILE NAME:
NOTE POUR LE TOME / VOLUME NOTE:

Conformationally constrained, fully synthetic macrocyclic compounds Macrocyclic natural and synthetic products have played a crucial role in the development of new drugs, especially as anti-infectives (F. von Nussbaum, M.
Brands, B. Hinzen, S. Weigand, D. Habich, Angew. Chem. Int. Ed. EngL 2006, 45, 5072-5129; D. Obrecht, J. A. Robinson, F. Bernardini, C. Bisang, S. J.
DeMarco, K.
Moehle, F. 0. Gombert, Curr. Med. Chem. 2009, 16, 42-65), as anti-cancer drugs and in other therapeutic areas (C. E. Ballard, H. Yu, B. Wang, Curr. Med.
Chem.
2002, 9, 471-498; F. Sarabia, S. Chammaa, A. S. Ruiz, L. M. Ortiz, F. J.
Herrera, Curr. Med. Chem. 2004, 11, 1309-1332). They often display remarkable biological activities, and many macrocycles or their derivatives have been successfully developed into drugs (L. A. Wessjohann, E. Ruijter, D. Garcia-Rivera, W.
Brandt, MoL
Divers. 2005, 9, 171-186; D. J. Newman, G. M. Gragg, K. M. Snader, J. Nat.
Prod.
2003, 66, 1022-1037). The chemical diversity of macrocyclic natural products is immense and provides a tremendous source of inspiration for drug design.
Macrocyclic natural and synthetic products generally exhibit semi-rigid backbone conformations placing appended substituents into well-defined spatial orientation.
Certain ring sizes are preferred (L. A. Wessjohann, E. Ruijter, D. Garcia-Rivera, W.
Brandt, MoL Divers. 2005, 9, 171-186), e.g. 16-membered rings are frequently found in oxygen-containing macrocycles, such as polyketides (M. Q. Zhang, B.
Wilkinson, Curr. Opin. BiotechnoL 2007, 18, 478-488). It is hypothesized that semi-rigid scaf-folds possess some of the favorable binding properties of rigid molecules (entropy), yet still retaining enough flexibility to adapt suitable conformations in the binding event (induced fit).
Macrocyclic natural and synthetic products are generally classified according to the chemical nature of the backbone, e.g. cyclic peptides (Y. Hamady, T. Shioiri, Chem.
Rev. 2005, 105, 4441-4482; N.-H. Tan, J. Zhou, Chem. Rev. 2006, 106, 840-895);

cyclic depsipeptides (F. Sarabia, S. Chammaa, A. S. Ruiz, L. M. Ortiz, F. J.
Herrera, Curr. Med. Chem. 2004, 11, 1309-1332); macrocyclic lactones (macrolactones) and macrolides; macrocyclic lactams (macrolactams), macrocyclic amines, macrocyclic ethers, macrocyclic ureas and urethanes, and others. The conformational, physico-chemical, pharmacological and pharmacodynamic properties of macrocyclic natural and synthetic compounds depend largely on the ring size, the chemical nature of the backbone, and of appended groups (L. A. Wessjohann, E. Ruijter, D. Garcia-Rivera, W. Brandt, Mol. Divers. 2005, 9, 171-186). By modifying these three parameters nature has created a virtually unlimited repertoire of molecular diversity.
Despite their - -

2 undisputed interesting biological properties, many natural products show limitations for drug development, such as low metabolic stability, i.e. short half lives, lack of or insufficient oral bioavailability as well as low tissue penetration and membrane permeability which renders them not amenable for intracellular targets. In addition, their high structural complexity imposes severe limitations to synthetic accessibility, often leaving fermentation or recombinant methods as sole options; thus making complex quality control and development processes necessary and leading to high production costs.
The present invention describes novel, fully synthetic, macrocyclic natural product-like molecules of type I (Scheme 1), accessible through a modular approach by connecting suitably protected building blocks A, B and C to a linear precursor followed by subsequent intramolecular cyclization.
Building blocks A serve as conformation-inducing templates ("Template") and are based on appropriately substituted and protected divalent biaryl-derivatives.
Biaryl as used in this context shall comprise all possible pairwise combinations of aromatic carbocyclic and/or aromatic heterocyclic ring systems connected by a C2¨C2 single bond, i.e. aryl¨aryl, heteroaryl¨heteroaryl, aryl¨heteroaryl and heteroaryl¨aryl.
Scheme 1: Macrocycles of Type I
A

X
a_R5 1:11 Building blocks B are corresponding to appropriately substituted and protected primary, secondary or tertiary aminoalcohols and are functioning as conformational

3 modulators ("Modulator") by influencing the conformation of the macrocycle, e.g.
through cis/trans-isomerization of amides.
Within the macrocycles backbone of I the building blocks A and B are connected via the "Bridge" C composed of one to three appropriately and independently substituted subunits c1, c2 and c3, which in turn are derived from suitably substituted and protected precursors, like, but not limited to, appropriately substituted and protected amino acids or amine derivatives.
Scheme 2: Building Blocks of Macrocycle I
"Template" A: "Modulator" B:

ira"R5 "Bridge" C comprised of up to three subunits c1-c3 (n=0-1):
\ 0 z 0 vo we u/
z = u =
The connectivity ¨X¨ between Template A and Modulator B is defined by an ether (X=0) or thioether (X=S) bond; while that between A and Bridge C is defined by the structural element ¨Y¨Z¨ as detailed below. As sulfur atoms of such a thioether linkage can easily and selectively be oxidized to the corresponding sulfoxides (S=0) or sulfones (S(=0)2), these higher oxidation states are also part of the invention.
Scheme 3: Connectivities of Macrocycle I (continued on the following page) x= z=

1\1 õ õ

4 Y¨Z =
_ R8 R8 0 R8 R9 Rio R9 H Rl 0 R7 ¨_ ¨1\1' - -Si-- -1¨[-- 1+-i % H R11 H R11H
/ N H u H u H - - t - t R8 0 R7 Rs R12 R7 R8 0 R7 0 R8 R12 I I / ,1 II II / II
NI

---S ---S ---S NI, ---S
H .
H H ' H , H H ' (13 i R8 0 R7 0 Rs Ri2 R7 ---S II N II
---S NI
0 H 0 H H ' U =

il R:NJ-1,- ,.)1 R130-.)__ V or W =

IL ,R7 R7,,,)-1 -. N Y '' R7'N'IjN'N.R7 ---H-Q, PH-- -, Rio Rii H R11 0 0 Rio H
The generic connection ¨Y¨Z¨ between A and C corresponds in most exemplified cases to a secondary or tertiary amide bond (¨C(=0)¨NR7¨). Alternative connectivi-ties ¨Y¨Z¨ are thioethers (¨S¨CHR8¨) and its oxidation products, i.e.
sulfoxides (¨S(=0)¨CHR8¨) or sulfones (¨S(=0)2¨CHR8¨), as well as olefinic moieties (¨(CHRg)t¨CR11=CR10¨) and their reduced aliphatic analogs (¨(CHR8)t¨CHR11¨
CHR1 ¨). Furthermore, in case of Templates A carrying a thiophenolic Y-group (Y=S) an additional two carbon spacer can be easily introcuded by reacting with (3-halo carboxyl or 13-halo carbonyl compounds prior to processing with the C building blocks;
thus providing access to ¨Y¨Z¨ groups of type ¨S¨CHR8¨C(=0)¨NR7¨, ¨S¨CHR8¨CHR12¨NR7¨, ¨S¨CHR8¨CHR12¨NR7¨ and their corresponding S-oxidized congeners.
-The functional moiety U connects Bridge C with the nitrogen atom of Modulator B. In most cases this is realized by an amide bond, in which case the moiety U
corresponds to a carbonyl group (¨C(=0)¨). Alternatively, U can be defined as a carbamoyl moiety (¨NR7¨C(=0)¨) leading to a urea (including the N-atom of B) as

5 functional connection between B and C. Similarly, a carboxyl group (-0¨C(=0)¨) as U describes a carbamate linkage between B and C. In addition, U can represent an oxalyl group (¨C(=0)¨C(=0)¨) or the corresponding acetal (¨C(-0R13)2¨C(=0)¨).
As mentioned before, the Bridge C itself comprises one to three (1-3) appropriately and independently substituted subunits cl , c2 and c3, which in turn are independently connected to each other by the generic groups V or W which can correspond to an amide bond (¨C(=0)NR7¨) and the corresponding inverse amide (¨NR7C(=0)¨), the methylene-heteroatom linkages ¨CHR8¨Q¨ and ¨Q¨CHR8¨, an alkene[1,2]diy1 moiety (¨CHR10=CHR11¨) or its reduced form as alkane[1,2]diy1 (¨CHR10¨CHR11¨), an oxalyl group (¨C(=0)¨C(=0)¨) or a disulfide bridge (¨S¨S¨).
The spatial orientation of the substituents in macrocycles I is modulated by the ring size and the stereochemical connectivity within building blocks A, B and C.
Therefore the macrocyclic backbone as well as the substituents contribute to the biological activity of compounds of type I.
Compounds of this invention are characterized by macrocyclic backbones containing an aromatic ether/thioether linkage and one or more tertiary amide bonds. In other cases secondary amide bonds, aliphatic ether linkages, ethylidene or ethylene moieties are exemplified as part of the backbone.
Ether linkages in macrocyclic molecules favorably influence physico-chemical and pharmacological properties, such as solubility in aqueous solutions, metabolic stability against proteolytic degradation, cell permeability and oral absorption (K. X.
Chen et al., J. Med. Chem. 2006, 49, 995-1005). In addition, tertiary amide bonds containing macrocycles are well-known for increased proteolytic stability, cell permeability and oral bioavailability compared to the parent molecules with secondary amide bonds (E. Biron, J. Chatterjee, 0. Ovadia, D. Langenegger, J. Brueggen, D.
Hoyer, H. A. Schmid, R. Jelinek, C. Gilon, A. Hoffmann, H. Kessler, Angew.
Chem.
Int. Ed. 2008, 47, 1-6; J. Chatterjee, 0. Ovadia, G. Zahn, L. Marinelli, A.
Hoffmann, C.
Gilon, H. Kessler, J. Med. Chem. 2007, 50, 5878-5881). For instance, the cyclic undecapeptide cyclosporin A (INN: Ciclosporin), which is used as

6 immunosuppressant in organ transplants, contains seven N-methylated amino acids and possesses good oral bioavailability when formulated appropriately (P. R.
Beauchesne, N. S. C. Chung, K. M. Wasan, Drug Develop. Ind. Pharm. 2007, 33, 211-220).
A well documented process in protein folding events is the peptidyl cis/trans isomerization of proline or pipecolic acid containing polypeptides and proteins. In vivo this process is mediated by peptidyl prolyl cis/trans isomerases such as the cyclophilins, the FK506-binding proteins and the parvulins (A. Bell, P.
Monaghan, A.
P. Page, mt. J. ParasitoL 2006, 36, 261-276). Besides their role in protein folding and in the immune system, peptidyl prolyl cis/trans isomerases have been implicated in cell cycle control (P. E. Shaw, EMBO Reports 2002, 3, 521-526) and therefore constitute interesting pharmaceutical targets. In the context of this invention it is worth mentioning that both FK506 and cyclosporin A are macrocyclic natural products interacting with the FK506-binding protein and cyclophilins, respectively.
An interesting structural motif found in several natural products consist of a macrocylic ring sytem with a biaryl moiety as backbone element. Such biaryls, which are composed of two aromatic or heteroaromatic rings connected via a single bond, are the outstanding characteristic of a number of antibacterial macrocyclic peptide classes, like the biphenomycins, arylomycins and aciculitins; not to mention the glycopeptide antibiotics with the vancomycins as most prominent representatives (L.
Feliu, M. Planas, Int. J. Pept. Res. Ther. 2005, 11, 53-97).
For many extra- and intracellular biological targets the quest for small molecule hits has been disappointing; this is especially true if protein-protein interactions are involved (J. A. Robinson, S. DeMarco, F. Gombert, K. Moehle, D. Obrecht, Drug Disc. Today 2008, 13, 944-951). These so-called "difficult targets" include e.g.
receptor tyrosine kinases, growth factor receptors, transcription modulators, and chaperones. Interestingly, several natural and synthetic macrocyclic compounds have been described as promising starting points for drug discovery programs around such difficult targets (D. Obrecht, J. A. Robinson, F. Bernardini, C. Bisang, S. J.
DeMarco, K. Moehle, F. 0. Gombert, Curr. Med. Chem. 2009, 16, 42-65).
The novel macrocycles of type I described in the embodiments of this invention are designed to combine unique features of natural macrocyclic compounds with beneficial physico-chemical and pharmacological properties of small molecules, e.g.:

7 = Natural product-like structural complexity = Good aequous solubility = High metabolic stability = Improved oral bioavailability = Enhanced membrane permeability = Extra- and intracellular targets amenable = Improved tissue penetration = Small molecule-like pharmacokinetics = Modular chemical synthesis = Synthesis process well suited for parallelization = Reasonable production costs = Small molecule-like QC and development processes The Main Embodiment of the current invention of novel and fully synthetic macrocyclic compounds I according Scheme 1 (detailed in Scheme 2 and Scheme 3) is defined by groups of selected building blocks A, B and C as shown in Table 1 to Table 3 and by the appending substituents R1-R57 as detailed below.
As shortly indicated before, Template A exerts an important conformational constraint on products of type I. These structural effects of A depend on (i) the dihedral angle between the two Csp2¨Csp2 connected aromatic rings AB and Ac that are defining the Template A entity; (ii) the relative orienFtation of the attachment vectors of ¨X¨ and ¨Y¨ and (iii) the spatial distance between the groups ¨X-- and ¨Y¨.
One possible general preparative access to the corresponding building blocks of type A consists of an C8p2¨C8p2-coupling between appropriately functionalized arene and/or heteroarenes (R. M. Kellogg et al., Org. Process Res. Dev. 2010, 14, 30-47; A.
de Meijere, F. Diederich (eds), Metal-Catalyzed Cross-Coupling Reactions, 2nd ed., Wiley-VCH 2004; especially for macrocyclic biaryls cf. Q. Wang, J. Zhu, Chimia 2011, 65, 168-174, and literature cited therein). Therefore the template A can be described by its two aryl/ heteroaryl constiuents AB and Ac, wherein AB is defined as that structural half of A that is directly connected with building block B and Ac as that half that is directly bound to building block C. In case of a biphenyl derivative as Template A such disconnection can be illustrated e.g. as:
_ _

8 Scheme 4: Dissection of Template A into its constituents AB and Ac A :

---- - i X' , Y._, 1=== AB>
.-- , R4 ___________________ I , , R2 R4¨ I Ac AB¨Ac R2 In general, Template A of this invention is a divalent radical that is defined by the combinatorial connection of its two constituent aryl/heterorayl moieties AB
and Ac selected from Table 1 and Table 2.
Table 1: Constituents AB1-AB65 of Template A (continued on the following pages) fL.

R3 li I/
I R3 ' i i Agi Ag2 Ag3 Ag4 X' R1 R3 i ,.,--- ,, /r), N
7...y...1-.--* R3 iR3 õ , -?Y )rY N"-1-"k-- N,,r,-,--N.,,x,.- R3 1 , ,.r.,, , ,

9 R1N ,....N R1 rx,.µ
ll ,,,---11 ______I
Yx-- R3----"------(7.--x-- R3- ----/-2--x-- R3-......r.;.N
R3 i i , R3 Ri R1 X Ri Ri.õ.õ,.... X , s N
l X ,s s ' X
I
I 1 I N 3 y,, N N >--, R3 R ' , 1 I R3 , , , -R1 N X,- Ri,) F21, 1,R1 -, N
) 3 R3 i R ' i , .

R3 N R1 R1 N X, ---L, ---.-: -r- .
N N R1--1,---N "r--- R3 N...r.,--.,,,--'. N

X-- ' i , , , , -R3 R1 X- X' R1-,LX... .,,R11R3 N --1,---- N
I I I
NNN N N N
R-, R3N IRli -"' NN ,.,R3 VN

V
N - N..kX" - 1 I 1 I
N,k.r.õ---,,,..- N,rõ---,,...----1-LX- ..**=T' i A i A
, 'y R1,....,,?...N,N ,N R1 .i. R1 N, N
N' 1 N
R3X- - R3- X- - "--_., NIi.., - X' µT-X .
i , i . , . .

N'X'=
N --- N N Ri 1 I 1 Ki N N

R3 Mx \ X I\' ---X'' m z X' , , , , , X- - R1 x- - - N-Q
R3.)<IVI INI -( R3- M J \_i R3-- -X, ' i , - !\IN,.. , R3---X, kiCIX-' It--R3 , X- -)F )=N
R3-"N
, , X- -R3"- IVI Ri X- - Ri X-CT N M
M N , i , N-N
r\i'Xi , , , Table 2: Constituents Ac1-Ac66 of Template A (continued on the following pages) ,, R÷---- I Y'-- , --'), --'--- 1 , I - I
R2 \R4 R"-- 'I._,R2 Ad 1 Ac2 Ac3 Ac4 I ¨RLI R4 R2/ Y"- R2 )--) '(=.,,r, N
R4 Yõ, R2 Ac5 Ac6 Ac7 Ac8 i FR"' R4 .--2('-- R4 RY.,._ N.;Th,-, I
R2 N1 R2N .. rõµi -.......õ..õ

A09 Ac10 Ac11 Ac12 , I I
R4, _.,I
X y Nõ.I.--Y-õ NY'"- N..
Y--, X

R4 R2--i' 4 R4 ....---**--*" R2 Ac13 A014 Ac15 Ac16 , I R4 ,1 i R2Y(Y-- R4 R 2 N Y I ' N...---,y,- -Ac17 Ac18 Ac19 Ac20 i N` R4-N
I /
,, -----1 I
R2.-).;,....õ, .N

Ac21 Ac22 Ac23 Ac24 i ,, i N Fr N
I Y''- ,,,,,A.,..õõXõ..
1 ,-LõN
N.,_,.õ N ,,..õ---, T R2 N R4 R4 NR2 IR' -N Y"

Ac25 Ac26 Ac27 Ac28 - _ , _ - =
_ Ni R4 NN 1\V N N.' N
R2 N Y _ R2 R2 R4- y 'Y"- 1 1 I
- y 'Y"- I

-Ac29 Ac30 Ac31 Ac32 R4,,, 11., IN
I I
I R4-N R2 -'rN N.R4 Ac33 Ac34 Ac35 Ac36 , , `I,, l',..
I I R .Y
4 õ.....- , R Y
, Y-ir ' 1 -..
NR2 NI:. ..---..
R2-N N R-, N N
T

Ac37 Ac38 Ac39 Ac40 . --N'' NIrel rilR
, 4 N-?-'''--- - yL ._ I ,I.,.N , NN
I
R2)N Y-N
R2 Y.
Ac41 Ac42 Ac43 Ac44 , , . .
, NN
*AR-2 )¨ M
R2 R4 Ra R2 R2 Ac45 Ac46 Ac47 Ac48 R4 ' R4T)Nm Ac49 Ac50 Ac51 Ac52 % / =
Q-N N-Q

Ac53 Ac54 Ac55 Ac56 , , , , Ac57 Ac58 Ac59 Ac60 RyNN R4--e-NNA
M N
N M
Mji )¨( Y- R2 Y- R2 Y¨

Ac61 Ac62 Ac63 Ac64 RNYS N\
N=N N¨N

Ac65 Ac66 The Modulator B is a divalent radical selected from the groups of Table 3. B1-B10 are optionally substituted primary or secondary amines carrying a moiety of type ¨CHR5¨LG, wherein LG is a suitable leaving group that can be replaced by the nucleophilic groups on Template A forming an ether (-0¨) or a thioether (-5¨) linkage (as well as its oxidized variations ¨S(=0)¨ and ¨S(=0)2¨) between building blocks of type A and B. Examples of appropriate LGs include ¨OH, which is in situ transformed into the active LG during Mitsunobu reactions, or halogens, like ¨Br or ¨I, which are amenable to SN reactions.
For most examples of this invention, the amine nitrogen of Modulator B forms a secondary or tertiary amide bond with the carboxyl group of the Bridge C. By virtue of inducing peptidyl cis-trans isomerizations or stabilizing cis amide bonds, building blocks of type B can function as conformational modulators in macrocycles of type I.
Table 3: Radicals B1-B10 (continued on the following page) NI

rc-H-R6 N) , The Bridge C is a divalent radical selected from the groups of Table 4. This divalent moiety C may consist of one to three (1-3) subunits c1 to c3, i.e. (i) ¨Z¨c1¨U¨, (ii) ¨Z¨c1¨V¨c2¨U¨ and (iii) ¨X¨cl¨V¨c2¨W¨c3¨U¨. As a consequence Bridge C
directly influences the ring size of the macrocycle and can therefore be regarded as spacer or linker. This Bridge C is joined to Template A via its terminal group Z (i.e. N-terminus in case of an amino acid) and to Modulator B via its terminal group U
(i.e. C-terminus in case of an amino acid) to form the macrocyclic ring of type L Thus C
contributes to the backbone of macrocycle I with its carbon chains as well as with its functional groups Z, W, V and U (cf. Scheme 2 and 3).
Table 4: Generic Representations of Bridge C

I I
---Z¨C¨C C U---- -Cl I I I I
C C V¨C C C U¨ -I I I I
R15 R17 _R19 R21 R23 R25 - ii I I I I I
C C V¨C C C W¨C C CU---I I I I I I I
R15 R17 JR19 o21 _rµ in rµ23 n25 1-127 m rµ29 n31 - -13 -n _p _ _n _ _p According to the preceding definitions, macrocycles I contain at least one amide bond or isosteric surrogate thereof. As emphasized in the introduction, tertiary amides generally show various ratios of cis and trans conformations in solution. In striking contrast secondary amides strongly prefer trans conformations. Such occurrence of cis and/or trans conformations in macrocyclic natural products containing tertiary amide groups is well documented. In some cases a rapid equilibration by peptidyl cis-trans isomerization is observed, whereas in other cases discrete cis and trans tertiary 5 amide bonds are detected as two stable conformers in solution at room temperature.
Consequently all possible stereoisomers, explicitly including atropisomers, con-formers or rotamers of macrocycles of type I are part of this invention.
The substituents attached to the Main Embodiment of macrocycle I or its constituents

10 A, B or C, are defined as follows:
R1 and R2 are independently defined as H; F; Cl; Br; I; CF3; OCF3; OCHF2;
NO2; CN; C1_24-alkyl; C2-24-alkenyl; C2_10-alkynyl; cycloalkyl;
heterocycloalkyl; aryl;
heteroaryl; aryl-C1_12-alkyl; heteroaryl-Ci_12-alkyl; ¨(CR32R33)q0R34;
¨(CR32R33),ISR34;
15 ¨(CR32R33)qNR7R36; ¨(CR32R33)q000NR7R36; ¨(CR32R330R7C00R36;
¨(CR32 R33)(1 NR7COR37; ¨(CR32 R33 ) NR7CONR7R36; ¨(CR32 R33) N R7S02 R38;
-(C R32 R33)q N R7S02N R7 R35; -(C R32 R33)qC00 R36; -(CR32R33)qCON R7 R35 ;
-(C R32 R33)qS02N R7R35; -(C R32 R33)qC0 R37; -(C R32 R33)qS 02R38; -(C R32 R33)q R39;
-(C R32 R33)q R4O.
, (C R32 R33)q R41; or ¨(CR32R33)c,R44;
R3 and R4 are independently defined as H; F; Cl; CF3; OCF3; OCHF2; NO2;
CN; C1_24-alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C1_12-alkyl;
heteroaryl-Ci_12-alkyl; C1_12-alkoxy or aryloxy;
R5 is H; CF3; C1_24-alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl;
aryl-C1_12-alkyl; or heteroaryl-C1_12-alkyl;
R6 is H; CF3; C1_24-alkyl; C2_24-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl; aryl-C1_12-alkyl; heteroaryl-C1_12-alkyl; ¨(CR32R33)q0R34;
¨(CR32R33)cISR34;
¨(CR32R33)qNR7R35; ¨(CR32R33)q000NR7R36; ¨(CR32R33),INR7COOR36;
¨(CR32R33)qNR7COR37; ¨(CR32R33)qNR7CONR7R36;¨(CR32R33),INR7S02R36;
¨(CR32R33)qNR7S02NR7R36;¨(CR32R33)qCOOR36; ¨(CR32R33)qCONR7R36;
¨(CR32R33)qS02NR7R36;¨(CR32R33)qCOR37; ¨(CR32R33)qS02R38; ¨(CR32R33)qR39;
¨(CR32R33)8R40; or ¨(CR32R33)q R41 ; or ¨(CR32R33),,R44;

R7 is H; C1_24-alkyl; C2_24-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1-12-alkyl; heteroaryl-C1_12-alkyl; or an N-protecting group;
R8 and R9 are independently defined as H; F; CF3; C1_24-alkyl; C2_24-alkenyl;
cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C1_12-alkyl; or heteroaryl-C1_12-alkyl;
R113, R11 and R12 are independently defined as H; C1_24-alkyl; or cycloalkyl;
R13 is Ci_24-alkyl or cycloalkyl;
R14, R2 and R26 are independently defined as H; F; CF3; C1-24-alkyl; C2_24-alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-Ci_12-alkyl;
heteroaryl-C1-12-alkyl; ¨(CR32R33)q0R34; ¨(CR32R33)cISR34; ¨(CR32R33)c1NR7R35;
¨(CR32R33)9000NR7R35;¨(CR32R33)qNR7C00R36; ¨(CR32R33)91\1R700R37;
¨(CR32R33)qNR7CONR7R35; ¨(CR32R33)qNR7S02R38; ¨(CR32R33)qNR7S02NR7R35;
¨(CR32R33)q000R38; ¨(CR32R33)qCONR7R35;¨(CR32R33)qS02NR7R35;
¨(CR32R33)qCOR37; ¨(CR32R33)qS02R38; ¨(CR32R33)qR39; ¨(CR32R33)8R43;
¨(CR32R33)pR41; or ¨(CR32R33)qR44;
R15, R17, R19, R21, R23, R25, R27, R29 and R31 are independently defined as H;
C1_24-alkyl; cycloalkyl; or heterocycloalkyl;
R16, R22 and R28 are independently defined as H; CF3; C1_24-alkyl;cycloalkyl;
heterocycloalkyl; aryl; heteroaryl; aryl-C1_12-alkyl; or heteroaryl-C1_12-alkyl;
R18, R24 and R3 are independently defined as H; F; CF3; C1-24-alkyl; C2-24-alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C1_12-alkyl;
heteroaryl-C1-12-alkyl; ¨(CR32R33)q0R34; ¨(CR32R33)qNR7R35; ¨(CR32R33)q000NR7R35;
¨(CR32R33)qNR7C00R36; ¨(CR32R33)qNR7C0R37; ¨(CR32R33)qNR7CONR7R35;
¨(CR32R33)qNR7S02R38; ¨(CR32R33)qNR7S02NR7R35; ¨(CR32R33),,000R36;
¨(CR32R33)qCONR7R35; ¨(CR32R33)qS02NR7R35; ¨(CR32R33)qCOR37; or ¨(CR32R33)ciR44;
R32 is H; F; CF3; C1_24-alkyl; C2_24-alkenyl; cycloalkyl; heterocycloalkyl;
aryl;
heteroaryl; aryl-C1-12-alkyl; heteroaryl-Ci_12-alkyl; ¨(CR51R53)q0R45;
¨(CR51R53)ciSR45;
¨(CR51R53)qNR7R45; ¨(CR51R53)q000NR7R45; ¨(CR51R53)qNR74COOR36;
¨(CR51R53)qNR700R37;¨(CR51R53)qNR700NR7R45; ¨(CR51R53)qNR7S02R38;

¨(CR51R53)qNR7S02NR7R45;¨(CR51R53)qCOOR36; ¨(CR51R53)qCONR7R45;
¨(CR51R53)qS02NR7R45; ¨(CR51R53),,COR37; ¨(CR51 R53)qS02R38; ¨(CR51R53)qR39;
¨(CR51R53)sR49; ¨(CR51R53)c,R41; or ¨(CR51R53),,R44;
R33 is H; C1_24-alkyl; C2_24-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1_12-alkyl; or heteroaryl-Ci_12-alkyl;
R34 is H; C1_24-alkyl; C2_24-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1-12-alkyl; heteroaryl-C1-12-alkyl; ¨(CR51R53)r0R45; ¨(CR51R53)rNR7R45;
¨(CR51R53)rOCONR7R35; ¨(CR51R53)rNR7COOR36; ¨(CR51R53)rNR7C0R38;
¨(CR51R53)rNR7CONR7R45; ¨(CR51R53)rNR7S02R38; ¨(CR51R53),ICOOR36;
¨(CR51R53)qCONR7R45; ¨(CR51R53)qS02NR7R45; ¨(CR51R53)qCOR38;
¨(CR51R53)qS02R38; ¨(CR51R53)qR39; ¨(CR51R53)sR4o; _(CR51R53)qR41; or ¨(CR51R53),,R44;
R35 is H; C1-24-alkyl; C2_24-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1_12-alkyl; heteroaryl-C1_12-alkyl; an N-protecting group;
¨(CR32R33),OR45;
¨(CR32R33)rNR7R45; ¨(CR32R33),OCONR7R45; ¨(CR32R33),NR7C00R36;
¨(CR32R33)rNR7CONR7R59; ¨(CR32R33),NR7S 02 R38 ; ¨ (C R32 R33) r N
R7S02NR7R59;
¨(CR32R33)qCOOR38; ¨(CR32R33)rNR7C0R37; ¨(CR32R33)qCONR7R58;
¨(CR32R33)qCOR37; ¨(CR32R33)qS02R38; ¨(CR32R33)qS02NR7R58; ¨(CR32R33)qR39;
¨(CR32R33)8R40; _(CR32R33)qR11; or ¨(CR32R33)qR44;
R36 is H; C1_24-alkyl; C2_24-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1_12-alkyl; heteroaryl-C1-12-alkyl; or an 0/S-protecting group;
R37 is C1_24-alkyl; C2_24-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1_12-alkyl; heteroaryl-C1_12-alkyl; ¨(CR51R53)q0R45; ¨(CR51R53)cISR45;
¨(CR51R53)qN R7R45; ¨(CR51R53)q000NR7R45; ¨(CR51R53),INR7C00R36;
¨(CR51R53),IN R7C0R38; ¨(CR51R53),INR7CONR7R45;¨(CR51R53),INR7S02R38;
¨(CR51R53)qNR7S02NR7R45;¨(CR51R53)qCOOR36; ¨(CR51R53),ICONR7R45;
¨(CR51R53),ISO2NR7R45;¨(CR51R53)1C0R44; ¨(CR51R53)ciSO2R38; ¨(CR51R53)tR39;
_(cR51R53)R4o; _(CR51R53)tR41; or ¨(CR51R53)tR44;
R38 is C1_24-alkyl; C2_24-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1-12-alkyl; or heteroaryl-C1_12-alkyl;

_ R39 is aryl; heteroaryl; ¨C6F12R3R4R46; or a group of one of the formulae H1-H34 listed in Table 5.
Table 5: Groups of Formulae H1-H34 (continued on the following page) ' R46 R46 N , R46 N R46 - - -rvi- - _ -M M M

, \ fi¨N N¨N ---" ¨
, Ra6 ----1\?"--R47 ---jrvi,--R47 t ---N

, , s'----- R46 N---- R46 -'---4N
tN D. ... ' " j ''',.:',', ,, 64 I -':1-'µ
--J\N õ...:.,-,...

1\r %---"-'"--N
- - N.;,=, -46 '-, N 47 N,1\1", R46 JJ =C =K N N
-- iN
*N R47 N .....---Ra6 N, = ,,c,N).,,N Ra6 / \ /
- - 1\1 R47 N R47 - - M
M

.

--. ¨
õ
--'7.-\ \ N--c-r -n/1)¨j M R46 m.,---Ra6 , , M

1 -"R46 --r7;)-- R46=.(7, _,¨R46 1-=N ---' N-,,.....)-..õ5-) I
-'(-7--.-- R46 ,;, I --1¨
N IN%....,,--.,N

, - - ¨

, ,N
m - --..------. D 46 -;--,..õ--N---, 46 il..... 1 ..:_=-....-R
N.. N -,- D46 ,L --R46 ,,I, .-'µ ----('*-, j,--T's R47 N N N
- N

, N-....----- R46 i-.
-- N

R4 is a group of one of formulae H35-H41 as shown in Table 6 below.
Table 6: Groups of Formulae H35-H41 ril .-/>
C N ) ,-N ,----N , N
e .R48 iµR.48 ,' \R48 ' l':z48 c=i) \ R49 / \ .,_ -`.. 3 R3 S¨N R m -X
,- ----N , ... R3 iR48 R48 ' FIR48 R41 is a group of one of formulae H42-H50 as shown in Table 7 below.
Table 7: Groups of Formulae H42-H50 (continued on the following page) , R49 , R49R49 L/ µµ R49 ¨1>
- --(_/) /) N --N N N
sR48 R49 \i___,, R49 ' s I.---'-c-------/\R3 R46 )-2/R3 N N
R48 R48 R48 R4 ¨NtReta, i'R48 R42 and R43 are independently defined as H; F; CF3; Ci_24-alkyl; C2_24-alkenyl;
cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C1_12-alkyl; or heteroaryl-C1-12-alkyl;
5 R44 is H; C1_24-alkyl; C2-24-alkenyl; cycloalkyl; heterocycloalkyl;
aryl; heteroaryl;
aryl-C1_12-alkyl; heteroaryl-Ci_12-alkyl; or a group of one of the formulae H51-H55 as shown in Table 8 below.
Table 8: Groups of Formulae H51-H55 (continued on the following page) - - - -6R52 - - ¨6 6 , , R15 RI, R17 R19 i ¨0-20 ¨ -q - -s - -q Li R51 NR45R7 R53 R51 Rlo I53 - - --c 6 ( , - -q- c - q R52 _ _-_. - - c _ ..q :=C C

- S - - q/R52 u u -R51- -R53- \
-----Ci\A¨

, , Ris R19 - -s - -si R52 u R45 is H; C1_24-alkyl; C2_24-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1-12-alkyl; heteroaryl-C1_12-alkyl; an N-protecting group;
¨(CR51R53)r0R38;
¨(CR51R53)rNR7R57; ¨(CR51R53)rOCONR7R57; ¨(CR51R53)rNR7CONR7R57;
¨(CR51R53)rNR7C0R38; ¨(CR51R53)rNR7S02NR7R57; ¨(CR51R53)rNR7S02R38;
¨(CR51R53)qCOOR36; ¨(CR51R53),ICOR38; ¨(CR51R53),ISO2R38; ¨(CR51R53)qR39;
¨(CR51R53)sR4o; _(CR51R53),,R41; or ¨(CR51R53)sR44;
R46 is H; F; CI; CF3; OCF3; OCHF2; NO2; CN; C1-24-alkyl; C2_24-alkenyl; C2_10-alkynyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C1_12-alkyl;
heteroaryl-C1-12-alkyl; ¨(CR51R53)q0R36; ¨(CR51R53),ISR36; ¨(CR51R53),INR7R57;
¨(CR51R53)q000NR7R57; ¨(CR51 R53),IN R7C00R36; ¨(CR51R530R7C0R38;
¨(CR51R53)qNR7CONR7R45; ¨(CR51R53),INR7S02R38; ¨(CR51R53),INR7S02NR7R45;
¨(CR51R53)qCOOR36; ¨(CR51R53)qCONR7R45;¨(CR51R53),ISO2NR7R45;
¨(CR51R53)qCOR38; ¨(CR51R53),ISO2R38; or ¨(CR51R53),,R44;
R47 is H; C1_24-alkyl; C2_24-alkenyl; C2_10-alkynyl; cycloalkyl;
heterocycloalkyl;
aryl; heteroaryl; aryl-C1_12-alkyl; heteroaryl-C1_12-alkyl; or ¨NR7R45;
R48 is H; C1_24-alkyl; C2_24-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1_12-alkyl; heteroaryl-C1_12-alkyl; an N¨protecting group;
¨(CR51R53)r0R45;
¨(CR51R53)rSR45; ¨(CR51R53)rNR7R45; ¨(CR51R53)rOCONR7R45;
¨(CR51R53)rNR7C00R38; ¨(CR51R53)rNR7COR38; ¨(CR51R53)rNR7CONR7R45;
¨(CR51R53)rNR7S02R38; ¨(CR51R53)rNR7S02NR7R45;¨(CR51R53)qCOOR36;
¨(CR51R53)qCONR7R45; ¨(CR51R53),S02NR7R45; ¨(CR51R53),COR38;
¨(CR51 R53)ciS 02 R38; or ¨(CR51R53)sR44;
R49 is H; C1-24-alkyl; C2-24-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1_12-alkyl; heteroaryl-C1_12-alkyl; ¨(CR51R53)q0R36; ¨(CR51R53),ISR36;

-(C R51 R53)q N R7R45; -(C R51 R53)q N R7C00R36; -(C R51 R53)q N R7C0R38;
-(CR51 R53)q N R7S02R38; -(C R51 R53)q N R7CON R7R45; -(C R51 R53)q000R36;
-(C R51 R53)qCON R7R45; -(C R51 R53)qC0 R38; or -(CR51R53)qR44;
R5 is H; C1_24-alkyl; Cm-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1.6-alkyl; heteroaryl-C1.6-alkyl; or an N-protecting group;
R51 and R53 are independently defined as H; F; CF3; C1-24-alkyl; C2_24-alkenyl;
cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C1_12-alkyl; heteroaryl-C1.12-alkyl;
¨(CR42R43)tOR36; ¨(CR42R43)MR7R57; ¨(CR42R43)tCOOR36; or ¨(CR42R43)1CONR7R57;
R52 is H; CF3; C1_24-alkyl; C2_24-alkenyl; cycloalkyl; heterocycloalkyl; aryl;

heteroaryl; aryl-C1_12-alkyl; heteroaryl-Ci_12-alkyl; ¨0R36; ¨NR7R57;
¨NR7COR38;
¨NR7COOR36; ¨NR7S02R38; ¨NR7CONR7R57; ¨000R36; ¨CONR7R57;
¨C(=NR7)NR7R57; ¨NR7C(=NR7)NR7R57; or a group of one of the formulae H56-H110 as shown in Table 9 below.
Table 9: Groups of Formulae H56-H110 (continued on the following pages) --*1 54 f-1,N.._N:=>
---V
\ V
\ V/

./-.\
---- _, /-)( R54 .4\11) N-J
N¨j N
\--N

R54 R54 R54 R5;¨..N
- µ,M
M

\1Th N

Nzz.(R54 NN
Fizz\
- 4N , M - - -S,=M - - 4N, fii - --N N

T-I¨T
R54 R54 T:::\
--Z

E¨T R54 ,/ .4- R T /17.),c R54 i--=\
,/ ),`,./
T ? T ' N---- -...,T 54 T-=-/ T=\ T
N¨ ¨N R54 N4 R54 R54 R54 T-Th R54 - - \ \. 1_4õ..i..õ1,-/;\
N..._. T

D54 )---Ii--" /7-- T 54 T\ R4 /---( - -Iv/
----NyN ---?----f N

- - \ Z --(----A) iR45 ¨1(?
___________________________________________ H H H
R56µ 02 DR. _R.
----,---_ R58 ( n _ _ R54 is H; F; CF3; OCF3; OCHF2; NO2; CN; C1_24-alkyl; C2_24-alkenyl; C2-10-alkynyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C1_12-alkyl;
heteroaryl-C1-12-5 alkyl; ¨0R36; ¨NR7R67; ¨NR7COR38; ¨NR7S02R38; ¨NR7CONR7R67; ¨00R38;
or ¨SO2R38;
- -R55 is H; CF3; C1_24-alkyl; C2_24-alkenyl; C2_10-alkynyl; cycloalkyl;
heterocycloalkyl; aryl; heteroaryl; heteroaryl-C1_12-alkyl; ¨000R36; or ¨CONR7R45;
5 R56 is H; F; CF3; C1-24-alkyl; C2_24-alkenyl; cycloalkyl;
heterocycloalkyl; aryl;
heteroaryl; aryl-C1_12-alkyl; heteroaryl-Ci_12-alkyl; ¨(CR42R43)s0 R36;
¨(C R42 R43)s N R7 R45; ¨(C R42 R43)qCOOR36; or ¨(CR42R43)qCONR7R45;
R57 is H; C1_24-alkyl; C2_24-alkenyl; cycloalkyl; aryl; aryl-C1_12-alkyl; or an N-protecting group.
Taken together, the following pairs of substituents can form optionally substituted cycloalkyl or heterocycloalkyl moieties: (R5 and R6); (R7 and R14); (R7 and R16); (R7 and R18); (R7 and R20); (R7 and R22); (R7 and R24); (R7 and R26); (R7 and R25); (R7 and R30); (R7 and R35); (R7 and R45); (R7 and R57); (R13 and R13); (R14 and R16);
(R14 and R18); (R15 and R51); (R19 and R51); (R2 and R22); (R2 and R24); (R26 and R25); (R26 and R30); (R32 and R33); (R42 and R43); or (R51 and R53).
In addition, the structural elements ¨NR7R35; or ¨NR44R45 can form one of the groups of formulae H111¨H118 as shown in Table 10 below.
Table 10: Heterocyclic Groups Defined by Linking the Residues of the Disubstituted Amino Groups ¨NR7R35 or ¨NR44R45.

- -N r - -N M

-a - -N T
(\) Generic atoms and connector groups in the aforementioned structures are:
Z, Y, X, W, V, U as defined by Scheme 3;

T is CR54 or N;
Q is 0; S; or NR35;
M is 0; S; or NR7.
The indices in the aforementioned structures are defined as:
m is an integer of 0-8;
n is an integer of 0-1;
p is an integer of 0-4;
q is an integer of 0-4;
r is an integer of 2-4;
s is an integer of 1-4;
t is an integer of 0-2;
u is an integer of 1-2.
For the avoidance of doubt, some of the aforementioned substituents, for example, but not limited to, R7, R16, R17, R18, R19, R22, R23, R24, R25, R28, R29, R30, R315 R32, R33, R42, R43, R45, R46, and R49; the indices as well as the generic atoms/connector groups (Z, Y, X, W, V, U, T, Q, M) can occur several times within the same molecular entity.
In such a case each of them shall be selected independently from others specified by the same symbol.
"Salts" as understood herein are especially, but not limited to, the pharmaceutically acceptable salts of compounds of formula I. Such salts are formed, for example, as acid addition salts with organic or inorganic acids, from compounds of type I
with a basic nitrogen atom. Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids; like acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adaman-tanecarboxylic acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane- or ethane-sulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1 ,2-disulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, 1,5-naphthalene-disulfonic acid, 2-, 3- or 4-methylbenzene-sulfonic acid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid, N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamic acid, or other organic protonic acids, such as ascorbic acid.
As used in this description, the term "alkyl", taken alone or in combinations (i.e. as part of another group, such as "aryl-C1_6-alkyl"), designates saturated, straight-chain or branched hydrocarbon radicals and may be optionally substituted. The term "C-alkyl" (x (x and y each being an integer) refers to an alkyl group as defined before containing x to y carbon atoms. For example a C1_6-alkyl group contains one to six carbon atoms. Representative examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like.
The term "alkenyl", taken alone or in combinations, designates straight chain or branched hydrocarbon radicals containing at least one or, depending on the chain length, up to four olefinic double bonds. Such alkenyl moieties are optionally substituted and can independently exist as E or Z configurations per double bond, which are all part of the invention. The term "C-alkenyl" (x and y each being an integer) refers to an alkenyl group as defined before, containing x to y carbon atoms.
The term "alkynyl" designates straight chain or branched hydrocarbon radicals containing at least one or, depending on the chain length, up to four triple bonds. The term "C-alkynyl" (x and y each being an integer) refers to an alkynyl group as defined before, containing x to y carbon atoms.
The term "cycloalkyl" refers to a saturated or partially unsaturated alicyclic moiety having from three to ten carbon atoms and may be optionally substituted.
Examples of this moiety include, but are not limited to, cyclohexyl, norbornyl, decalinyl and the like.
The term "heterocycloalkyl" describes a saturated or partially unsaturated mono- or bicyclic moiety having from two to nine ring carbon atoms and one or more ring heteroatoms selected from nitrogen, oxygen or sulphur. This term includes, for example, morpholino, piperazino, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, octahydro-1H-indolyl, 1,7-diazaspiro[4.4]nonane and the like. Said heterocycloalkyl ring(s) might be optionally substituted.

The term "aryl", taken alone or in combinations, designates aromatic carbocyclic hydrocarbon radicals containing one or two six-membered rings, such as phenyl or naphthyl, which may be optionally substituted by up to three substituents such as F, Cl, Br, CF3, OH, OCF3, OCHF2, NH2, N(CH3)2, NO2, CN, Ci_s-alkyl, C2-6-alkenyl, alkynyl, phenyl or phenoxy.
The term "heteroaryl", taken alone or in combinations, designates aromatic heterocyclic radicals containing one or two five- and/or six-membered rings, at least one of them containing up to four heteroatoms selected from the group consisting of 0, S and N and whereby the heteroaryl radicals or tautomeric forms thereof may be attached via any suitable atom. Said heteroaryl ring(s) are optionally substituted, e.g.
as indicated above for "aryl".
The term "aryl-Cx_ralkyl", as used herein, refers to an Cx_ralkyl group as defined above, substituted by an aryl group, as defined above. Representative examples of aryl-Cx_ralkyl moieties include, but are not limited to, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and the like.
The term "heteroaryl-Cx_ralkyl", as used herein, refers to an Cx_ralkyl group as defined above, substituted by a heteroaryl group, as defined above. Examples of heteroaryl-Cx_ralkyl groups include pyridin-3-ylmethyl, (1H-pyrrol-2-yl)ethyl and the like.
The terms "alkoxy" and "aryloxy", taken alone or in combinations, refer to the groups of -0-alkyl and -0-aryl respectively, wherein an alkyl group or an aryl group is as defined above. The term "C8-alkoxy" (x and y each being an integer) refers to an -0-alkyl group as defined before containing x to y carbon atoms attached to an oxygen atom. Representative examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy and the like. Examples of aryloxy include e.g.
phenoxy.
"Amino" designates primary, secondary or tertiary amines. Particular secondary and tertiary amines are alkylamines, dialkylamines, arylamines, diarylamines, arylalkyl-amines and diarylamines wherein the alkyl or aryl is as herein defined and optionally substituted.

The term "N-protecting group", as use herein, refers to the following commonly known groups, suitable to protect a nitrogen atom: allyloxycarbonyl (Alloc), tert-butoxy-carbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), 2-or 4-nitrobenzenesulfonyl (Ns), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), 2,2,2-Trichloro-ethoxycarbonyl (Troc), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DM B), triphenylmethyl (trityl, Tr), or 2-chlorotrityl (CTC).
The term "0/S-protecting group", as use herein, refers to the following commonly known groups, suitable to protect either an oxygen and/or a sulfur atom: tert-butyldimethylsilyl(TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl (Ac), pivaloyl (Piv), tert-butyl, 2-(trimethylsilyl)ethoxymethyl (S EM), methoxymethyl (MOM), triphenyl-methyl (trityl, Tr), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMB), or 2-(Trimethylsilyl)ethyl (TMSE).
A person skilled in the art might find easily corresponding equivalents for the above mentioned protecting groups which are considered to be as well comprised by the gist of the current invention. Examples of suitable protecting groups are as detailed in P.G.M. Wuts, T.W. Greene, Greene's Protective Groups in Organic Synthesis, John Wiley and Sons, 4th Edition, 2006.
The term "optionally substituted" is in general intended to mean that a group, such as, but not limited to Cx_ralkyl, C"-alkenyl, Cx_y-alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, Cx_y-alkoxy and aryloxy may be substituted with one or more substituents independently selected from amino (-NH2), dimethylamino, nitro (-NO2), halogen (F, Cl, Br, l), CF3, cyano (-CN), hydroxy, methoxy, ethoxy, phenyloxy, benzyloxy, acetoxy, oxo (=0), carboxy, carboxamide, methyl, ethyl, n-propyl, iso-propyl, cyclo-propyl, phenyl, benzyl, sulfonic acid, sulfate, phosphonic acid, phosphate, phosphonate, or ¨SRa, ¨S(0)R, ¨S(0)2R8, ¨Ra, ¨C(0)Ra, ¨C(0)0Ra, ¨C(0) N RbiRc, ¨C(= N Ra)N
RbR.c, ¨0Ra, ¨0C(0)Ra, ¨0C(0)0Ra, ¨0C(0)N RbiRc, ¨0S(0)Ra, _0S(0)2R, ¨0S(0)N RbiRc, ¨OS (0)2N Rb Rc, NRbRc, ¨N RaC(0)Rb, ¨N RaC(0)0Rb, ¨N RaC(0)NRbRc, ¨N RaC(=N Rd) N RbiRc, ¨NRaS(0)Rb, ¨N RaS(0)2Rb, wherein Ra, Rb, Rc, and Rd are each independently hydrogen, C1_6-alkyl, C2_6-alkenyl, C2.6-alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl as described herein; or Rb and RC may be taken together with the N-atom to which they are attached forming heterocycloalkyl or heteroaryl. These groups in turn can be substituted with one or more moieties selected from the group consisting of halogen (F, Cl, Br, or l), hydroxyl, amino, mono-, di- or tri-C1_6-alkylamino, mono-, di- or tri-arylamino, hydroxy, carboxy, C1_6-alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate.
5 As used herein, all groups that can be substituted in one embodiment are indicated to be "optionally substituted", unless otherwise specified.
The embodiments of the present invention shall include so-called "prodrugs" of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds, which in vivo are readily convertible into the required compound.
10 Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Hans Bundgaard, Design of Prodrugs, Elsevier, 1985; and in Valentino J. Stella et al., Prodrugs: Challenges and Rewards, Springer, 1st ed., 2007.
15 The term "isomer" comprises species of identical chemical formula, constitution and thus molecular mass, such as but not limited to C=C-double bond or amide cis/trans isomers, rotamers, conformers and diastereomers.
All possible stereoisomers - explicitly including atropisomers - conformers and 20 rotamers as well as salts, solvates, clathrates, N-oxides, or isotopically enriched or enantiomerically enriched versions of the macrocycles of type I are part of this invention.
In a Preferred Embodiment of this invention, macrocycles of type I are defined by 25 groups of selected building blocks A, B and C and substituents R1-R57.
The connectivities between the building blocks of the preferred embodiment are defined as shown in Scheme 5.
Scheme 5: Connectivities of Preferred Embodiment of Macrocycle I (continued on the 30 following page) x= z=

- -S- -S.

= . = -Y¨Z =

- - - --H
OH 8 HHt R"
- --S I I
1\1, -S
H R'"H
- - H H H
u=
RN) R13Oç

W; V =

, R7 R7 R7 HQ.
H' 8 R18 R" HR11 0, Rl H
The biaryl Template A of the Preferred Embodiment is selected from Agl¨Ac1; Ag1¨Ac2; A81¨Ac3; Ag1¨Ac4; Ag1¨Ac5; Agl¨Ac6; A81¨Ac8;
A1¨Ac9; AB1¨Ac1 1; AB1¨Ac12; A81¨Ac13; AB1¨Ac19; AB1¨A622; AB1¨Ac24;
Ag1¨Ac49; Ag1¨Ac51; A82¨Ac1; A82¨Ac2; AB2¨Ac3; AB2¨Ac4; A82¨A05; AB2¨Ac11;
AB2¨Ac12; A82¨Ac51; AB3¨Ac 1; A83¨A02; AB3¨A03; AB3¨Ac4; AB3¨Ac5; AB3¨Ac11;
AB3¨Ac12; AB4¨Ac1; A84¨Ac2; AB4¨Ac3; A34¨Ac4; AB4¨Ac5; A84¨Ac6; AB4¨Ac11;
AB4¨Ac12; A84¨Ac19; AB4¨Ac22; A84¨Ac24; A84¨Ac49; AB4¨Ac51; A84¨Ac59;
AB5¨Ac1; A85¨A02; AB5¨Ac3; AB5¨Ac4; A85¨Ac5; AB5¨Ac11; A85¨Ac12; A85¨A051;
AB5¨A059; A36¨Ac1; A86¨Ac4; AB6¨Ac8; AB6¨A09; AB6¨Ac11; A86¨A013; A86¨A016;
AB6¨A018; A56¨Ac19; A86¨A020; A56¨Ac30; A86¨Ac31; AB6¨Ac49; AB6¨Ac51;
AB9¨Ac6; A89¨Ac49; Ag10¨Ac6; AB11¨Ac6; A812¨A02; A812¨Ac5; A812¨Ac11;
AB12¨Ac12; AB13¨A02; AB13¨Ac5; A813¨Ac11; AB13¨Ac12; AB13¨Ac5; A813¨Ac11;
Ag13¨Ac12; A814¨Ac49; A820¨Ac2; AB20¨Ac6; AB20¨Ac49; A823¨A04; AB23¨A049;
AB26¨Ac2; AB26¨Ac5; AB26¨Ac11; AB26¨Ac12; A840¨Ac2; A840¨Ac5; AB40¨Ac11;

AB40¨Ac12; A345¨Ac49; AB45¨Ac52; A545¨Ac57; AB45¨Ac58; AB45¨Ac65;
AB45¨Ac66; AB46¨Ac57; AB46¨Ac58; AB47¨Ac58; AB49¨Ac49; A850¨Ac57;
AB50¨Ac58; AB50¨Ac61; AB51¨Ac49; AB51¨Ac61; AB53¨Ac2; AB53¨Ac5; AB53¨Ac11;
AB53¨Ac12; A358¨Ac2; A958¨Ac5; AB58¨Ac11; AB58¨Ac12; AB59¨Ac2; AB59¨Ac5;
A59¨Ac1 1; AB59¨Ac12; or AB59¨Ac61 The preferred Modulator B is selected from B1; B4; B5; B6; B7; B8; B9 or B10;
and the preferred Bridge C from = 10 Cl ; C2; or C3.
The substituents R1-R67 attached to the Preferred Embodiment of macrocycle I
are as defined as shown below.
R1 and R2 are independently defined as H; F; Cl; Br; I; CF3; OCF3; OCHF2;
NO2; CN; C1_6-alkyl; C2_6-alkenyl; C2.6-alkynyl; cycloalkyl; heterocycloalkyl;
aryl-C1-6-= alkyl; heteroaryl-C1_6-alkyl; ¨(CR32R33),I0R34; ¨(CR32R33)cISR34;
¨(CR32R33)c,NR7R36;
¨(CR32R33)q000NR7R35; ¨(CR32R33)c,NR7COOR36; ¨(CR32R33),INR7C0R37;
¨(CR32R33),INR7CONR7R36; ¨(CR32R33)qNR7S02R38; ¨(CR32R33),INR7S02NR7R36;
¨(CR32R33),,COOR36; ¨(CR32R33),ICONR7R35;¨(CR32R33),,S02NR7R36;
¨(CR32R33)qCOR37; ¨(CR32R33),ISO2R38; ¨(CR32R33)qR39; ¨(CR32R33),,R40;
¨(CR32R33)qR41; or ¨(CR32R33),,R44;
R3 and R4 are independently defined as H; F; Cl; CF3; OCF3; OCHF2; NO2;
CN; C1_6-alkyl; cycloalkyl; C1_6-alkoxy or aryloxy;
R5 is H; CF3; C1_6-alkyl; or cycloalkyl;
R6 is H; CF3; C1-6-alkyl; C2_6-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl; aryl-C1_6-alkyl; heteroaryl-C1_6-alkyl; ¨(CR32R33),10R34;
¨(CR32R33),ISR34;
¨(CR32R33),INR7R35; ¨(CR32R33)q000NR7R35; ¨(CR32R33)qNR7C00R36;
¨(CR32R33)qNR7C0R37; ¨(CR32R33)qNR7CONR7R35; ¨(CR32R33),INR7S02R38;
¨(CR32R33)qNR7S02NR7R35;¨(CR32R33)q000R36; ¨(CR32R33)qCONR7R36;
¨(CR32R33),ISO2NR7R36;¨(CR32R33)qCOR37; ¨(CR32R33),ISO2R38; ¨(CR32R33),,R39;
¨(CR32R33)3R40; ¨(CR32R33)qR41; or ¨(CR32R33)qR44;

R7 is H; Cis-alkyl; C2.6-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
heteroaryl-C1.6-alkyl; or an N-protecting group;
R8 and R9 are independently defined as H; CF3; C1_6-alkyl; cycloalkyl;
heterocycloalkyl;
R10, R11 and R12 are independently defined as H; Cis-alkyl; or cycloalkyl;
R13 is C1_6-alkyl;
R14, R2 and R26 are independently defined as H; F; CF3; C1_6-alkyl; C2-6-alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-Ci_s-alkyl;
heteroaryl-C1-6-alkyl; ¨(CR32R33),10R34; ¨(CR321:233) S R34; ¨(C R32 R33 )cl NR7R35;
¨(CR32R33)q000NR7R35; ¨(CR32R33)qNR7C00R36; ¨(CR32R33)qNR7C0R37;
¨(CR32R33)qNR7CONR7R35; ¨(CR32R33)qNR7S02R38; ¨(CR32R33)qNR7S02NR7R35;
¨(CR32R33)qCOOR36; ¨(CR32R33)qCONR7R35;¨(CR32R33),ISO2NR7R35;
¨(CR32R33),,COR37; ¨(CR32R33),ISO2R38; ¨(CR32R33)qR39; ¨(CR32R33)8R49;
¨(CR32R33)ciR41; or ¨(CR32R33)qR44;
R15, R17, R19, R21, R23, R26, R27, R29 and R31 are independently defined as H;
or C1_6-alkyl;
R16, R22 and R28 are independently defined as H; CF3; or C1_6-alkyl;
R18, R24 and R3 are independently defined as H; F; CF3; C1_6-alkyl; C2-6-alkenyl; cycloalkyl; heterocycloalkyl; aryl-Ci_s-alkyl; heteroaryl-C1.6-alkyl;

¨(CR32R33)q0R34; ¨(CR32R33)(INR7R35; ¨(CR32R33)(1000NR7R35;
¨(CR32R33)qNR7C00R36; ¨(CR32R33)qNR7C0R37; ¨(CR32R33)qNR700NR7R35;
¨(CR32R33),INR7S02R38; ¨(CR32R33)qNR7S02NR7R35;¨(CR32R33)qCOOR36;
¨(CR32R33)qCONR7R35;¨(CR32R33)qS02NR7R35; ¨(CR32R33)qCOR37; or ¨(CR32R33)qR44;
R32 is H; F; CF3; C1-6-alkyl; C2_6-alkenyl; cycloalkyl; heterocycloalkyl;
aryl;
heteroaryl; aryl-C1.6-alkyl; heteroaryl-C1_6-alkyl; ¨(CR42R51)q0R45;
¨(CR42R51)cISR45;
¨(CR42R51)õ1NR7R45; ¨(CR42R51)q000NR7R45; ¨(CR42R51)qNR7C00R36;
¨(CR42R51)ciNR7C0R38;¨(CR42R51)ciNR700NR7R45; ¨(CR42R51)c,NR7S02R38;

¨(CR42R51),INR7S02NR7R45;¨(CR42R51)qCOOR36; ¨(CR42R51)qCONR7R45;
¨(CR42R51)qS02NR7R45;¨(CR42R51)qCOR38; ¨(CR42R51),ISO2R38; ¨(CR42R51),R39;
¨(CR42R51).R49; ¨(CR42R51),,R41; or ¨(CR42R51)qR44;
R33 is H; or C1_6-alkyl;
R34 is H; C2_6-alkenyl; cycloalkyl; aryl; heteroaryl; aryl-C1_6-alkyl;
heteroaryl-C1_6-alkyl; ¨(CR42R51)r0R45; ¨(CR42R51)rNR7R45;
¨(CR42R51)r000NR7R35;
¨(CR42R51),NIR7C00R36; ¨(CR42R51)rNR7C0R38; ¨(CR42R51)rNR7CONR7R45;
¨(CR42R51)rNR7S02R35; ¨(CR42R51)cCOOR36; ¨(CR42R51)qCONR7R45;
¨(CR42R51)qS02NR7R45; ¨(CR42R51)qCOR38; ¨(CR42R51),ISO2R35; ¨(CR42R51)q R35;
_ ¨(CR42R5i)sR4o., (CR42R51)qR41; or ¨(CR42R51),,R44;
R35 is H; C1.6-alkyl; C2_6-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1_6-alkyl; heteroaryl-C1_6-alkyl; an N-protecting group;
¨(CR32R33),OR45;
¨(CR32R33)rNR7R45; ¨(CR32R33),OCONR7R45; ¨(CR32R33)rNR7C00R36;
¨(CR32R33),NR7C0R37; ¨(CR32R33)rNR7CONR7R45; ¨(CR32R33)rNR7S02R38;
¨(CR32R33),NR7S02NR7R45; ¨(CR32R33)qCOOR36; ¨(CR32R33)qCONR7R45;
¨(CR32R33)qCOR37; ¨(CR32R33)ciS 02 R38 ; R32 R33 )qS 02 NR7R56; ¨(CR32 R33) q R39;
¨(CR32R33).R40; ¨(CR32R33)qR41; or ¨(CR32R33)qR44;
R36 is H; C1_6-alkyl; cycloalkyl; aryl; aryl-C1_6-alkyl; or an 0/S-protecting group;
R37 is C1_6-alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl;
heteroaryl-C1_6-alkyl; ¨(CR42R51)q0R45; ¨(CR42R51)cISR45; ¨(CR42R51)qNR7R45;
¨(CR42R51).000NR7R45; ¨(CR42R51).NR7C00R36; ¨(CR42R51)c1NR7C0R44;
¨(CR42R51)5NR7CONR7R45;¨(CR42R51).NR7S02R38; ¨(CR42R51)sNR7S02NR7R45;
¨(CR42R51)qCOOR36; ¨(CR42R51)qCONR7R45;¨(CR42R51)qS02NR7R45;
¨(CR42R51)tCOR38; ¨(CR42R51)qS02R33; ¨(CR42R51)tR39; ¨(CR42R51),,R40;
¨(CR42R51)tR41; or ¨(CR42R51)tR44;
R38 is C1.6-alkyl; C2_6-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl; aryl-Ci_6-alkyl; or heteroaryl-C1_6-alkyl;
R39, R40, and R41 are as defined in the Main Embodiment;

R42 and R43 are independently defined as H; F; CF3; C1_6-alkyl; Cm-alkenyl;
cycloalkyl; heterocycloalkyl; aryl-C1.6-alkyl; or heteroaryl-C1_6-alkyl;
R44 is H; C1_6-alkyl; C2.6-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
5 aryl-Ci_6-alkyl; heteroaryl-C1_6-alkyl; or a group of one of the formulae H51-H55 as shown in Table 8 above.
R45 is H; C1_6-alkyl; C2_6-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1..6-alkyl; heteroaryl-C1.6-alkyl; an N-protecting group;
¨(CR42R51)r0R36;
10 ¨(CR42R51),NR7R57; ¨(CR42R51)rOCONR7R57; ¨(CR42R51),NR7CONR7R57;
¨(CR42R51)rNR7C0R38; ¨(CR42R51),NR7S02R38; ¨(CR42R51)rNR7S02NR7R57;
¨(CR42R51),ICOOR36; ¨(CR42R51),ICOR38; ¨(CR42R51),,,S02R33; ¨(CR42R51),,R39;
¨(CR42R51).R40; ¨(CR42R51)qR41; or ¨(CR42R51)8R44;
15 R46 is H; F; Cl; CF3; OCF3; OCHF2; NO2; CN; C1_6-alkyl; C2_6-alkenyl; 02-alkynyl; cycloalkyl; heterocycloalkyl; aryl-Ci_6-alkyl; heteroaryl-C1_6-alkyl;
¨(CR42R51)q0R36; ¨(CR42R51)cS R36; -(C R42R51)q NR7R57; ¨(CR42R51)q000NR7R57;
¨(CR42R51)qNR44COOR36; ¨(CR42R51)qNR7COR38; ¨(CR42R51)qNR7CONR7R45;
¨(CR42R51)ciNR7S02R38; ¨(CR42R51),INR7S02NR7R45; ¨(CR42R51)q000R36;
20 ¨(CR42R51)qCONR7R45;¨(CR42R51)qS02NR7R45; ¨(CR42R51)cCOR38;
¨(CR42R51),ISO2R38; or ¨(CR42R51),,R44;
R47 is H; 01.6-alkyl; C2_6-alkenyl; C2_6-alkynyl; cycloalkyl;
heterocycloalkyl; aryl-01.6-alkyl; heteroaryl-C1_6-alkyl; or ¨N R7R45;
R48 is H; C1_6-alkyl; C2_6-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1_6-alkyl; heteroaryl-Ci_6-alkyl; an N¨protecting group;
¨(CR42R51)r0R45;
¨(CR42R51)rS R45; -(CR42R51)rN R7R45; -(CR42R51)rOCON R7R45;
-(CR42R51)rNR7COOR38; -(CR42R51)1N R7C0R38; -(CR42R51)rNR700N R7R45;
¨(CR42R51)rNR7S02R38; ¨(CR42R51)rNR7S02NR7R45;¨(CR42R51)qCOOR36;
¨(CR42R51)qCONR7R45; ¨(CR42R51)rSO2NR7R45; ¨(CR42R51)qCOR38;
¨(CR42R51)c,S02R38; or ¨(CR42R51)sR44;
R49 is H; C1-6-alkyl; C2_6-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-Ci..6-alkyl; heteroaryl-C1_6-alkyl; ¨(CR42R51)q0R36; ¨(CR42R51)cS R36;
¨(CR42 R510 R7R45; -(CR42R51)qN R7000R36; -(CR42R51)qNR7COR38;

-¨(CR42R51),NR7S02R38; ¨(CR42R51)qNR7CONR7R45; ¨(CR42R51)q000R36;
¨(CR42R51)qCONR7R45; ¨(CR42R51)qCOR38; or ¨(CR42R51)qR44;
R50 is H; C1.6-alkyl; C2_6-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1_6-alkyl; heteroaryl-C1_6-alkyl; or an N-protecting group;
R51 and R53 are independently defined as H; F; CF3; C1-6-alkyl; C2.6-alkenyl;
cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C1.6-alkyl; heteroaryl-C1_6-alkyl;
¨(CR42R43)tOR36; ¨(CR42R43)tN R7R57; ¨(CR42R43)tCOOR36; or ¨(CR42R43)1CONR7R57;
R52 is H; CF3; C2.6-alkenyl;
cycloalkyl; heterocycloalkyl; aryl;
heteroaryl; heteroaryl-C1.6-alkyl; ¨0R36; ¨NR7R57; ¨NR7COR38;
¨NR7COOR36; ¨NR7S02R38; ¨NR7CONR7R57; ¨000R36; ¨CONR7R57;
¨C(=NR7)NR7R57; ¨NR7C(=NR7)NR7R57; or a group of one of the formulae H56-H110 as shown in Table 9 above.
R54 is H; F; CF3; OCF3; OCHF2; NO2; CN; C1_6-alkyl; C2_6-alkenyl; C2_6-alkynyl;
cycloalkyl; heterocycloalkyl; aryl-C1.6-alkyl; heteroaryl-C1_6-alkyl; ¨0R36;
¨NR7R57;
¨NR7COR38; ¨NR7S02R38; ¨NR7CONR7R57; ¨00R38; or ¨SO2R38;
R55 is H; CF3; C1_6-alkyl; C2_6-alkenyl; C2_6-alkynyl; cycloalkyl;
heterocycloalkyl;
aryl; heteroaryl; aryl-C1_6-alkyl; heteroaryl-C1-6-alkyl; ¨000R36; or ¨CONR7R45;
R56 is H; F; CF3; C1.6-alkyl; C2.6-alkenyl; cycloalkyl; heterocycloalkyl;
aryl;
heteroaryl; aryl-C1_6-alkyl; heteroaryl-C1_6-alkyl; ¨(CR42R43)80R36;
¨(CR42R43)8NR7R45;
¨(CR42R43)qCOOR36; or ¨(CR42R43),,CONR7R45;
R57 is H; C1-6-alkyl; C2.6-alkenyl; cycloalkyl; aryl-C1_6-alkyl; or an N-protecting group.
Defined as for the Main Embodiment (vide supra) are i) the generic atoms and connector groups Z, Y, X, W, V, U, T, 0 and M; ii) the indices m, n, p, q, r, s, t and u;
as well as iii) pairs of substituents that can be define additional cyclic structural elements.

In a Further Preferred Embodiment of this invention, the macrocycles of type I
are defined by groups of selected building blocks A, B and C and substituents R1-R57 as follows. The connectivities between these building blocks are defined as for the Preferred Embodiment and as shown in Scheme 5 above.
The biaryl Template A of the Further Preferred Embodiment is selected from AB1¨Acl; AB1¨Ac4; AB1¨Ac6; AB1¨Ac8; AB1¨Ac9; AB1¨Ac11; AB1¨Ac13;
Agl¨Ac19; Aal¨Ac22; A51¨Ac24; AB1¨Ac49; AB1¨Ac51; AB2¨Ac4; AB2¨Ac51;
AB4¨Ac1; AB4¨Ac4; AB4¨Ac6; AB4¨Ac19; AB4¨Ac22; AB4¨Ac24; AB4¨Ac49;
AB4¨Ac51; AB4¨Ac59; AB5¨Ac51; AB5¨Ac59; AB6¨Ac1; AB6¨Ac4; AB6¨Ac8; AB6¨Ac9;
AB6¨Ac11; A36¨Ac13; AB6¨Ac16; AB6¨Ac18; AB6¨Ac19; AB6¨A020; AB6¨Ac30;
AB6¨Ac31; AB6¨Ac49; AB6¨Ac51; AB9¨Ac6; AB9¨Ac49; AB14¨Ac49; AB20¨Ac6;
AB20¨Ac49; AB23¨Ac4; AB23¨Ac49; AB45¨Ac49; AB45¨Ac52; AB45¨Ac57;
AB45¨Ac58; AB45¨Ac65; AB45¨Ac66; AB46¨Ac57; AB46¨Ac58; AB49¨Ac49;
AB50¨Ac57; AB50¨Ac58; AB50¨Ac61; AB51¨Ac49; AB51¨Ac61; or A59¨A61.
The further preferred Modulator B is selected from BI; B4; B5; B6; or B7;
and the further preferred Bridge of type C from C1; C2; or C3.
The substituents R1-R57 attached to the Further Preferred Embodiment of macrocycle I are as defined as described below.
R1 and R2 are independently defined as H; F; Cl; Br; I; CF3; OCF3; OCHF2;
NO2; CN; C1_6-alkyl; C2.6-alkenyl; C2.6-alkynyl; cycloalkyl; heterocycloalkyl;
aryl-C1-6-alkyl; heteroaryl-C1_6-alkyl; ¨(CR32R33)90R34; ¨(CR32R33)cISR34;
¨(CR32R33)qNR7R35;
¨(CR32R33)q000NR7R35; ¨(CR32R33),IN R7C00 R36; ¨(CR32R33),INR7COR37;
¨(CR32R33)qN R7CONR7R35; ¨(CR32R33)qNR7S02R38; ¨(CR32R33)q000R36;
¨(CR32R33),ICONR7R35; ¨(CR32R33)qS02NR7R35; ¨(CR32R33)qCOR37; ¨(CR32R33)q R39;
¨(CR32R33)qR40; ¨(CR32R33)qR41; or ¨(CR32R33)qR44.
R3 and R4 are independently defined as H; F; Cl; CF3; OCF3; OCHF2; NO2;
CN; C1-6-alkyl; or C1_6-alkoxy;

R5 is H; CF3; or C1_6-alkyl;
R6 is H; CF3; C1.6-alkyl; Cm-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl; aryl-C1_6-alkyl; heteroaryl-C1_6-alkyl; ¨(CR32R33)90R34;
¨(CR32R33)cISR34;
¨(CR32R33),INR7R35; ¨(CR32R33)9000NR7R35; ¨(CR32R33)qNR7COOR36;
¨(CR32R33)qN R7C0R37; ¨(CR32R33),INR7CONR7R35;¨(CR32R33),INR7S02R38;
¨(CR32R33)qCOOR36; ¨(CR32R33)qCONR7R35;¨(CR32R33)c,S02NR7R35;
¨(CR32R33)qCOR37; ¨(CR32R33)qR39; ¨(CR32R33)8R40; ¨(CR32R33)qR41; or ¨(CR32R33),,R44;
R7, R8, R9, R10, R11, R12 and R13 are defined as in the Preferred Embodiment;
R14, R2 and R26 are independently defined as H; F; CF3; C1_6-alkyl; C2-6-alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C1_6-alkyl;
heteroaryl-C16-alkyl; ¨(CR32R33),40R34; ¨(CR32R33),ISR34; ¨(CR32R33),INR7R35;
¨(CR32R33)q000NR7R35;¨(CR32R33)qNR7C00R36; ¨(CR32R33)qNR7C0R37;
¨(CR32R33)qN R7CONR7R35; ¨(CR32R33) NR7S02R38; ¨(CR32R33)qCOOR36;
¨(CR32R33)qCONR7R35;¨(CR32R33),ISO2NR7R35;¨(CR32R33)qCOR37; ¨(CR32R33),,R39;
¨(CR32R33)8R40; ¨(CR32R33)qR41; or ¨(CR32R33)c,R44;
R15, R16, R17, R19, R21, R22, R23, R25, R27, R28, R29 and R31 are defined as in the Preferred Embodiment;
R18, R24 and R3 are independently defined as H; F; CF3; C1.6-alkyl; C2-6-alkenyl; cycloalkyl; heterocycloalkyl; aryl-C1_6-alkyl; heteroaryl-C1_6-alkyl;
¨(CR32R33)q0R34; ¨(CR32R33)qNR7R35; ¨(CR32R33)(1000NR7R35;
¨(CR32R33)qN R7C00R36; ¨(CR32R33)(INR7C0R37; ¨(CR32R33),INR7CONR7R35;
¨(CR32R33)qNR7S02R38; ¨(CR32R33)qCOOR36; ¨(CR32R33)qCONR7R35;
¨(CR32R33)qCOR37; or ¨(CR32R33),,R44;
R32 is H; F; CF3; Cie-alkyl; C2_6-alkenyl; cycloalkyl; heterocycloalkyl; aryl;

heteroaryl; aryl-C1_6-alkyl; heteroaryl-C1_6-alkyl; ¨(CR42R43)q0R45;
¨(CR42R43),ISR45;
¨(CR42R43)qNR7R45; ¨(CR42R43),INR7C00R36; ¨(CR42R43)qNR7C0R38;
- R42R43)qCOOR36; ¨(CR42R43),,CONR7R45; ¨(CR42R43),,COR38; ¨(CR42R43)qR39;
¨(CR42R43).R40; ¨(CR42R43)qR41; or ¨(CR42R43)9R44;

R33 is H; or C1_6-alkyl;
R34 is H; C1_6-alkyl; C2.6-alkenyl; cycloalkyl; aryl; heteroaryl; aryl-C1_6-alkyl;
¨(CR42R43)r0R45; ¨(CR42R43)rN R46; ¨(C R42 R43) rOCO N R36;
¨(CR42R43)rN R7C00 R36; ¨(CR42R43)rN R7C0 R38; ¨(CR42R43)1N R7CON R7R46;
¨(CR42R43)rN R7S02R38; ¨(C R42R43)qC00 R36; ¨(CR42R43)qCON R46;
¨(CR42R43)qC0 R38; ¨(C R42R43)q R39; ¨(CR42 R43),R4 ; ¨(C R42R43)q R41; or ¨(CR42R43),,R44;
R35 is H; C1_6-alkyl; C2.6-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1.6-alkyl; heteroaryl-C1.6-alkyl; an N-protecting group;
¨(CR32R33)r0R45;
¨(CR32R33)rNR7R45; ¨(CR32R33)rOCONR7R45; ¨(CR32 R33) r N R7C00 R36;
¨(CR32R33)rN R7C0 R37; ¨(CR32R33)rN R7C0 N R60; ¨(C R32 R33)rN R7S02R38;
¨(C R32R33)qC00 R36; ¨(CR32R33)qCON R7R46; ¨(CR32R33)qC0 R38; ¨(CR32R33)q R39;
1 5 ¨(C R32 R33),R46; ¨(C R32R33)q R41 ; or ¨(CR32R33)qR44;
R36 is H; Ci_6-alkyl; cycloalkyl; aryl; aryl-C1_6-alkyl; or an 0/S-protecting group;
R37 is C1_6-alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-Ci.6-alkyl;
heteroaryl-C1_6-alkyl; ¨(CR42R43)q0R45; ¨(CR42R43),ISR45; ¨(CR42R43),INR7R45;
¨(CR42R43)9OCONR7R45; ¨(CR42R43)9NR7C00R36; ¨(CR42R43)8NR7COR44;
¨(CR42R43)sNR7CONR7R45; ¨(CR42R43)8NR7S02R38; ¨(CR42R43)qCOOR36;
¨(CR42R43)qCON R7R46; ¨(C R42R43)tC 0 R38 ; ¨(C R42 R43)tR39 ; ¨(C R42 R43), R46;
¨(C R42 R43)tR41; or ¨(CR42R43)tR44;
R38, R42, R43 and Rare defined as in the Preferred Embodiment;
R39, R40, and R41 are as defined in the Main Embodiment;
R45 is H; C1-6-alkyl; C2.6-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1.6-alkyl; heteroaryl-C1_6-alkyl; an N-protecting group;
¨(CR42R43)r0R36;
¨(CR42R43)rN R7R67; ¨(CR42R43)rOCON R67; ¨(CR42R43)rN R7C0 N R67;
_ (CR42R43)rN
R7C0 R38; ¨(C R42 "43' )rN R7S02R38; ¨(C R42R43)qC00 R36;
¨(C R42 R43)qC0 R38; ¨(C R42 R43)q R39; ¨(C R42 R43)sr140 =
(C R42R43)q R41; or ¨(CR42R43).R44;

R46 is H; F; Cl; CF3; OCF3; OCHF2; NO2; CN; Cm-alkyl; C2_6-alkenyl; C2_6-alkynyl; cycloalkyl; heterocycloalkyl; aryl-Cm-alkyl; heteroaryl-C1.6-alkyl;
¨(CR42R43),I0R36; ¨(CR42R43)qNR7R57; ¨(CR42R43),INR7C0R38; ¨(CR42R43),COOR36;
¨(CR42R43)qCONR7R45;¨(CR42R43),ISO2NR7R45; ¨(CR42R43)9COR38; or ¨(CR42R43),,R44;

R47 is H; C1-6-alkyl; C2.6-alkenyl; C2.6-alkynyl; cycloalkyl;
heterocycloalkyl; aryl-Cm-alkyl; heteroaryl-Ci.6-alkyl; or ¨NR7R45.
R4 is H; Cm-alkyl; C2_6-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
10 aryl-Cm-alkyl; heteroaryl-Cm-alkyl; an N¨protecting group;
¨(CR42R43),OR45;
¨(CR42R43)rSR45; ¨(CR42R43)rNR7R45; ¨(CR42R43),OCONR7R45;
¨(CR42R43)rNR7C00R36; ¨(CR42R43)rNR700R38; ¨(CR42R43)rNR7CONR7R45;
¨(CR42R43)rNR7S02R38; ¨(CR42R43)qCOOR36; ¨(CR42R43)qCONR7R45;
¨(CR42R43)qCOR38; or ¨(CR42R43)8R44;
R49 is H; Cm-alkyl; C2_6-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-Cm-alkyl; heteroaryl-Cm-alkyl; ¨(CR42R43)q0R36; ¨(CR42R43),INR7R45;
¨(CR42R43),INR7C0R38; ¨(CR42R43)qNR7S02R38; ¨(CR42R43)qCOOR36;
¨(CR42R43)qCONR7R45; ¨(CR42R43),COR38; or ¨(CR42R43),,R44;
R5 is H; Cm-alkyl; C2_6-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-Cm-alkyl; heteroaryl-Cm-alkyl; or an N-protecting group;
R51 and R53 are independently defined as H; F; CF3; Cm-alkyl; C2_6-alkenyl;
cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-Cm-alkyl; heteroaryl-C1_6-alkyl;
- R42R43) , _toR36. (CR42R43)tNR7R57; ¨(CR42R43)tCOOR36; or ¨(CR42R43)100NR7R57;
R52 is defined as in the Preferred Embodiment;
R54 is H; F; CF3; OCF3; OCHF2; NO2; CN; Cm-alkyl; C2_6-alkenyl; C2..6-alkynyl;
cycloalkyl; heterocycloalkyl; aryl-Ci_6-alkyl; heteroaryl-Cm-alkyl; ¨0R36;
¨NR7R57;
¨NR7COR38; ¨NR7S02R38; ¨NR7CONR7R57; ¨00R38; or ¨SO2R38;
R55 is H; CF3; C1-6-alkyl; C2_6-alkenyl; C2_6-alkynyl; cycloalkyl;
heterocycloalkyl;
aryl; heteroaryl; aryl-Cm-alkyl; heteroaryl-Cm-alkyl; ¨000R36; or ¨CONR7R45;

R56 is H; F; CF3; C1_6-alkyl; C2_6-alkenyl; cycloalkyl; heterocycloalkyl;
aryl;
heteroaryl; aryl-C1_6-alkyl; heteroaryl-C1_6-alkyl; ¨(CR42R43).0R36;
¨(CR42R43)8NR7R45;
¨(CR42R43),,COOR36; or ¨(CR42R43)qCONR7R45;
R57 is is defined as in the Preferred Embodiment;
as are (vide supra)i) the generic atoms and connector groups Z, Y, X, W, V, U, T, and M; ii) the indices m, n, p, q, r, s, t and u; as well as iii) the pairs of substituents that can be define additional cyclic structural elements.
In a Particularly Preferred Embodiment of this invention, the macrocycles of type I are defined by groups of selected building blocks A, B and C and substituents R1-R57 as follows. The connectivities between these building blocks are defined as for the Preferred Embodiment and as shown in Scheme 5 above.
The biaryl Template A of the Particularly Preferred Embodiment is selected from AB 1¨Ac1 ; AB 1¨Ac4 ; AB1¨Ac19; AB2¨Ac4; AB4¨Ac 1; AB4¨Ac4 ; AB4¨Ac 19 ;
AB4¨Ac59; AB5¨Ac51; AB5¨Ac59; AB6¨Ac31; A89¨Ac6; or AB46¨Ac58.
The particularly preferred Modulator building block of type B and the Bridge of type C
are selected as descriped in the Further Preferred Embodiment.
The substituents R1-R57 attached to the Particularly Preferred Embodiment of macrocycle I are as defined as described below.
R1 and R2 are defined as in the Further Preferred Embodiment;
R3 and R4 are independently defined as H; F; CF3; OCF3; OCHF2; CN; or C1-6-alkoxy;
R5 is H; CF3; or Ci_6-alkyl;
R6 is defined as in the Further Preferred Embodiment;
R7, Rs, R9, R10, R11, R12 and R13 are defined as in the Preferred Embodiment;

R14, R29 and R26 are defined as in the Further Preferred Embodiment;
R15, R16, R17, R19, R21, R22, R23, R25, R27, R28, R29 and R31 are defined as in the Preferred Embodiment, R18, R24, R3o and R32 are defined as in the Further Preferred Embodiment;
R33 is H; or C1_6-alkyl;
R34, R35, R36 and R37 are defined as in the Further Preferred Embodiment;
R38, R42, R43 and R44 are defined as in the Preferred Embodiment;
R39, R40, and R41 are as defined in the Main Embodiment;
R45 is defined as in the Further Preferred Embodiment;
R46 is H; F; CI; CF3; OCF3; OCHF2; NO2; CN; Ci_6-alkyl; C2.6-alkenyl; C2-6-alkynyl; cycloalkyl; heterocycloalkyl; aryl-C1_6-alkyl; heteroaryl-Ci_6-alkyl;
or ¨(CR42R43)qR44;
R47 is H; C1-6-alkyl; C2_6-alkenyl; C2_6-alkynyl; cycloalkyl;
heterocycloalkyl; aryl-Ci_6-alkyl; heteroaryl-C1.6-alkyl; or ¨NR7R45;
R48 is defined as in the Further Preferred Embodiment;
R49 is H; C1-6-alkyl; C2-6-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1.6-alkyl; heteroaryl-C1.6-alkyl; or ¨(CR42R43)qR";
R59 is defined as in the Further Preferred Embodiment;
R51 and R53 are independently defined as H; F; CF3; C1.6-alkyl; Cm-alkenyl;
cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C1_6-alkyl; heteroaryl-C1_6-alkyl;
¨(CR42R43)10R36; ¨(CR42R43)1NR7R57; ¨(CR42R43)tCOOR36; or ¨(CR42R43)tCONR7R57;
R52 is defined as in the Preferred Embodiment;

R54 is H; F; CF3; OCF3; OCHF2; NO2; CN; C1-6-alkyl; C2-6-alkenyl; C2.6-alkynyl;
cycloalkyl; heterocycloalkyl; aryl-C1.6-alkyl; heteroaryl-C1-alkyl; ¨0R36;
¨NR7R57;
¨NR7COR38; ¨NR7S02R38; ¨NR7CONR7R57; ¨00R38; or ¨SO2R38;
R55 is H; CF3; C1_6-alkyl; C2_6-alkenyl; C2.6-alkynyl; cycloalkyl;
heterocycloalkyl;
aryl; heteroaryl; aryl-C1.6-alkyl; heteroaryl-C1_6-alkyl; ¨000R36; or ¨CONR7R45;
R56 is H; F; CF3; C1_6-alkyl; C2_6-alkenyl; cycloalkyl; heterocycloalkyl;
aryl;
heteroaryl; aryl-C1_6-alkyl; heteroaryl-C1_6-alkyl; ¨(CR42R43)80R36;
¨(CR42R43)8NR7R45;
¨(CR42R43)qCOOR36; or ¨(CR42R43)qCONR7R45;
R57 is is defined as in the Preferred Embodiment;
as are (vide supra)i) the generic atoms and connector groups Z, Y, X, W, V, U, T, Q
and M; ii) the indices m, n, p, q, r, s, t and u; as well as iii) the pairs of substituents that can be define additional cyclic structural elements.
In an Specific Representation of the Particularly Preferred Embodiment the Bridge C is represented by --- CAA

wherein CAA is an amino acid selected from the readily accessible amino acids listed in Table

11. Even though only one stereoisomer, usually the L-enantiomer, is cited within Table 11, it is understood that the complementary enantiomer is also part to the embodiment. Also not listed explicitly, but part of the embodiment are the simple N-methyl derivatives of the listed amino acids.
Table 11: Structures representing subunits CAA of Bridge C (continued on the following pages) Code Chemical Name Ala L-Alanine Code Chemical Name Arg L-Arginine Asn L-Asparagine Asp L-Aspartic acid Cys L-Cysteine Glu L-Glutamic acid Gin L-Glutamine Gly Glycine His L-Histidine Ile L-Isoleucine Leu L-Leucine Lys L-Lysine Met L-Methionine Phe L-Phenylalanine Pro L-Proline Ser L-Serine Thr L-Threonine Trp L-Tryptophan Tyr L-Tyrosine Val L-Valine Apa 3-Amino-propanoic acid H-133-HAla-OH (3S)-3-Amino-butyric acid H-I33-HVal-OH (3R)-3-Amino-4-methyl-valeric acid H-133-HIle-OH (3R, 4S)-3-Amino-4-methyl-hexanoic acid H-I33-HLeu-OH (3S)-3-Amino-5-methyl-hexanoic acid H-133-HMet-OH (3S)-3-Amino-5-methylthio pentanoic acid H-03-HTyr-OH (3S)-3-Amino-4-(4'-hydroxyphenyI)-butyric acid H-133-HHis-OH (3S)-3-Amino-4-(imidazole-4'-yI)-butyric acid H-133-HPhe-OH (3S)-3-Amino-4-phenyl butyric acid H-r33-HTrp-OH (3S)-3-Amino-4-(indo1-3'-y1)-butyric acid H-133-HSer-OH (3R)-3-Amino-4-hydroxy-butyric acid H-I33-HAsp-OH 3-Amino-pentanedioic acid H-f33-HG1u-OH (3S)-3-Amino-hexanedioic acid H-133-H Lys-OH (3S)-3,7-Diamino-heptanoic acid Code Chemical Name H-133-HArg-OH (3S)-3-Amino-6-guanidino-hexanoic-acid H-f33-HCys-OH (3R)-3-Amino-4-mercapto-butyric acid H-133-HAsn-OH (3S)-3-Amino-4-carbamoyl-butyric acid H-133-HGIn-OH (3S)-3-Amino-5-carbamoyl-pentanoic acid H-133-HThr-OH (3R,4R)-3-Amino-4-hydroxy-pentanoic acid Gaba 4-Amino-butyric acid H-y4-D1HAla-OH (4S)-4-Amino-pentanoic acid H-y4-DiHVal-OH (4R)-4-Amino-5-methyl-hexanoic acid H-y4-DiHIle-OH (4R, 5S)-4-Amino-5-methyl-heptanoic acid H-y4-DiHLeu-OH (4R)-4-Amino-6-methyl-heptanoic acid H-y4-DiHMet-OH (4R)-4-Amino-6-methylthio-hexanoic acid H-y4-DiHTyr-OH (4R)-4-Amino-5-(4'-hydroxypheny1)-pentanoic acid H-y4-DiHHis-OH (4R)-4-Amino-5-(imidazole-4'-y1)-pentanoic acid H-y4-DiHPhe-OH (4R)-4-Amino-5-phenyl-pentanoic acid H-y4-DiHTrp-OH (4R)-4-Amino-5-(indo1-3'-y1)-pentanoic acid H-y4-DiHSer-OH (4R)-4-Amino-5-hydroxy-pentanoic acid H-y4-DiHAsp-OH (4R)-4-Amino-hexanedioic acid H-y4-DiHGIu-OH 4-Amino-heptanedioic acid H-y4-DiHLys-OH (4S)-4,8-Diamino-octanoic acid H-y4-DiHArg-OH (4S)-4-Amino-7-guanidino-heptanoic-acid H-y4-DiHCys-OH (4R)-4-Amino-5-mercapto-pentanoic acid H-y4-DiHAsn-OH (4R)-4-Amino-5-carbamoyl-pentanoic acid H-y4-DiHGIn-OH (3S)-3-Amino-5-carbamoyl-hexanoic acid H-y4-D1HThr-OH (4R, 5R)-4-Amino-5-hydroxy-hexanoic acid Cit L-Citrulline Orn L-Ornithine tBuA L-t-Butylalanine Sar Sarcosine Pen L-Penicillamine tBuG L-tert-Butylglycine 4AmPhe L-para-Aminophenylalanine 3AmPhe L-meta-Aminophenylalanine 2AmPhe L-ortho-Aminophenylalanine Code Chemical Name Phe(mC(NH2)=NH) L-meta-Amidinophenylalanine Phe(pC(NH2)=NH) L-para-Amidinophenylalanine Phe(mNHC(NH2)=NH) L-meta-Guanidinophenylalanine Phe(pNHC(NH2)=NH) L-para-Guanidinophenylalanine 2Pal (2S)-2-Amino-3-(pyridine-2'-yI)-propionic acid 4Pal (2S)-2-Amino-3-(pyridine-4'-yI)-propionic acid Phg L-Phenylglycine Cha L-Cyclohexylalanine Caal L-3-Cyclobutylalanine C5a1 L-3-Cyclopentylalanine Nle L-Norleucine 2-Nat L-2-Naphthylalanine 1-Nal L-1-Naphthylalanine 4CIPhe L-4-Chlorophenylalanine 3CIPhe L-3-Chlorophenylalanine 2CIPhe L-2-Chlorophenylalanine 3,4Cl2Phe L-3,4-Dichlorophenylalanine 4FPhe L-4-Fluorophenylalanine 3FPhe L-3-Fluorophenylalanine 2FPhe L-2-Fluorophenylalanine Thi L13-2-Thienylalanine Tza L-2-Thiazolylalanine Mso L-Methionine sulfoxide AcLys N-Acetyllysine Dap 2,3-Diaminopropionic acid Dab 2,4-Diaminobutyric acid Dbu (2S)-2,3-Diamino-butyric acid Abu y-Aminobutyric acid (GABA) Aha E-Am inohexa no ic acid Aib a-Aminoisobutyric acid ACC 1-Amino cyclopropane carboxylic acid ACBC 1-Amino cyclobutane carboxylic acid ACPC 1-Amino cyclopentane carboxylic acid 1-ACHC 1-Amino cyclohexane carboxylic acid Code Chemical Name 2-ACHC 2-Amino cyclohexane carboxylic acid 3-ACHC 3-Amino cyclohexane carboxylic acid 4-ACHC 4-Amino cyclohexane carboxylic acid Y(BzI) L-O-Benzyltyrosine H(BzI) (3S)-2-Amino-3-(1'-benzylimidazole-4'-y1)-propionic acid Bip L-(4-phenyl)phenylalanine S(BzI) L-O-Benzylserine T(BzI) L-O-Benzylthreonine alloT (2S, 3S)-2-Amino-3-hydroxy-butyric acid Leu3OH (2S, 3R)-2-Amino-3-hydroxy-4-methyl-pentanoic acid hAla L-Homo-alanine hArg L-Homo-arginine hCys L-Homo-cysteine hGlu L-Homo-glutamic acid hGln L-Homo-glutamine hHis L-Homo-histidine hIle L-Homo-isoleucine hLeu L-Homo-leucine hNle L-Homo-norleucine hLys L-Homo-lysine hMet L-Homo-Methionine hPhe L-Homo-phenylalanine hSer L-Homo-serine hThr L-Homo-threonine hTrp L-Homo-tryptophan hTyr L-Homo-tyrosine hVal L-Homo-valine hCha L-Homo-cyclohexylalanine Bpa L-4-Benzoylphenylalanine OctG L-Octylglycine Tic (3S)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid Tiq (1S)-1,2,3,4-Tetrahydroisoquinoline-1-carboxylic acid Oic (2S, 3aS, 7aS)-1-Octahydro-1H-indole-2-carboxylic acid 4AmPyrrl (2S, 4S)-4-Amino-pyrrolidine-2-carboxylic acid Code Chemical Name 4AmPyrr2 (2S, 4R)-4-Amino-pyrrolidine-2-carboxylic acid 4PhePyrri (2S, 4R)-4-Phenyl-pyrrolidine-2-carboxylic acid 4PhePyrr2 (2S, 4S)-4-Phenyl-pyrrolidine-2-carboxylic acid 5PhePyrri (2S, 5R)-5-Phenyl-pyrrolidine-2-carboxylic acid 5PhePyrr2 (2S, 5S)-5-Phenyl-pyrrolidine-2-carboxylic acid 4Hypl (4S)-L-Hydroxyproline 4Hyp2 (4R)-L-Hydroxyproline 4Mpl (4S)-L-Mercaptoproline 4Mp2 (4R)-L-Mercaptoproline Pip L-Pipecolic acid H-83-HCit-OH (3S)-3-Amino-6-carbamidyl-hexanoic acid H-83-HOrn-OH (3S)-3,6-Diamino-hexanoic acid H-133-HtBuA-OH (3S)-3-Amino-5,5-dimethyl-hexanoic acid H-83-HSar-OH N-Methyl-3-amino-propionic acid H-f33-HPen-OH (3R)-3-Amino-4-methy1-4-mercapto-pentanoic acid H-133-HtBuG-OH (3R)-3-Amino-4,4-dimethyl-pentanoic acid H-83-H4AmPhe-OH (3S)-3-Amino-4-(4'-aminophenyI)-butyric acid H-83-H3AmPhe-OH (3S)-3-Amino-4-(3'-aminopheny1)-butyric acid H-83-H2AmPhe-OH (3S)-3-Amino-4-(2'-aminophenyI)-butyric acid H-83-HPhe(mC(NH2)=NH)-OH (3S)-3-Amino-4-(3'-amidinopheny1)-butyric acid H-83-HPhe(pC(NH2)=NH)-OH (3S)-3-Amino-4-(4'-amidinophenyI)-butyric acid H-83-HPhe(mNHC(NH2)=
NH)-OH (3S)-3-Amino-4-(3'-guanidinophenyI)-butyric acid H-83-HPhe(pNHC(NH2)=
NH) OH (3S)-3-Amino-4-(4'-guanidino-phenyl)-butyric acid H-83-H2Pal-OH (3S)-3-Amino-4-(pyridine-2'-y1)-butyric acid H-83-H4Pal-OH (3S)-3-Amino-4-(pyridine-4'-yI)-butyric acid H-f33-HPhg-OH (3R)-3-Amino-3-phenyl-propionic acid H-133-HCha-OH (3S)-3-Amino-4-cyclohexyl-butyric acid H-83-HC4al-OH (3S)-3-Amino-4-cyclobutyl-butyric acid H-133-HC5a1-0H (3S)-3-Amino-4-cyclopentyl-butyric acid Code Chemical Name H-133-HNIe-OH (3S)-3-Amino-heptanoic acid H-133-H2Nal-OH (3S)-3-Amino-4-(2'-naphthyl)-butyric acid H-r33-H1Nal-OH (3S)-3-Amino-4-(1'-naphthyl)-butyric acid H-133-H4CIPhe-OH (3S)-3-Amino-4-(4'-chlorophenyI)-butyric acid H-133-H3C1Phe-OH (3S)-3-Amino-4-(3'-chloropheny1)-butyric acid H-f33-H2CIPhe-OH (3S)-3-Amino-4-(2'-chloropheny1)-butyric acid H-P3-H3,4C12Phe-OH (3S)-3-Amino-4-(3',4'-dichloropheny1)-butyric acid H-133-H4FPhe-OH (3S)-3-Amino-4-(4'-fluorophenyI)-butyric acid H-133-H3FPhe-OH (3S)-3-Amino-4-(3'-fluorophenyI)-butyric acid H-133-H2FPhe-OH (3S)-3-Amino-4-(2'-fluoropheny1)-butyric acid H-f33-HThi-OH (3R)-3-Amino-4-(2'-thienyI)-butyric acid H-133-HTza-OH (3R)-3-Amino-4-(2'-thiazolyI)-butyric acid H-I33-HMso-OH (3R)-3-Amino-4-methylsulfoxyl-butyric acid H-f33-HAcLys-OH (3S)-7-Acetylamino-3-amino-heptanoic acid H-133-HDpr-OH (3R)-3,4-diamino-butyric acid H-I33-HA2Bu-OH (3S)-3,5-Diamino-pentanoic acid H-133-HDbu-OH (3R)-3,4-Diamino-pentanoic acid H-133-HAib-OH Amino-dimethyl acetic acid H-f33-HCyp-OH 1-Amino-cyclopentane-1-yl-acetic acid H-133-HY(Bz1)-OH (3S)-3-Amino-4-(4'-benzyloxypheny1)-butyric acid H-133-HH(BzI)-OH (3S)-3-Amino-4-(1'-benzylimidazole-4'-y1)-butyric acid H-63-HBip-OH (3S)-3-Amino-4-biphenylyl-butyric acid H-133-HS(Bz1)-OH (3S)-3-Amino-4-(benzyloxy)-butyric acid H-f33-HT(SzI)-OH (3R, 4R)-3-Amino-4-benzyloxy-pentanoic acid H-P-HalloT-OH (3R, 4S)-3-Amino-4-hydroxy-pentanoic acid H-133-HLeu30H-OH (3R, 4R)-3-Amino-4-hydroxy-5-methyl-hexanoic acid H-f33-HhAla-OH (3S)-3-Amino-pentanoic acid H-63-HhArg-OH (3S)-3-Amino-7-guanidino-heptanoic acid H-03-HhCys-OH (3R)-Amino-5-mercapto-pentanoic acid H-f33-HhGlu-OH (3S)-3-Amino-heptanedioic acid H-63-HhGln-OH (3S)-3-Amino-6-carbamoyl hexanoic acid H-f33-HhHis-OH (3S)-3-Amino-5-(imidazole-4'-yI)-pentanoic acid H-f33-HhIle-OH (3S, 5S)-3-Amino-5-methyl-heptanoic acid Code Chemical Name H-133-HhLeu-OH (3S)-3-Amino-6-methyl-heptanoic acid H-03-HhNle-OH (3S)-3-Amino-octanoic acid H-83-DiAoc-OH (3S)-3,8-Diamino-octanoic acid H-83-HhMet-OH (3S)-3-Amino-6-methylthio-hexanoic acid H-133-HhPe-OH (3S)-3-Amino-5-phenyl-pentanoic acid H-133-HhSer-OH (3S)-3-Amino-5-hydroxy-pentanoic acid H-f33-HhThr-OH (3S, 5R)-3-Amino-5-hydroxy-hexanoic acid H-83-HhTrp-OH (3S)-3-Amino-5-(indo1-3'-y1)-pentanoic acid H-83-HhThr-OH (3S)-3-Amino-5-(4'-hydroxyphenyl)-pentanoic acid H-83-HhCha-OH (3S)-3-Amino-5-cyclohexyl-pentanoic acid H-133-HBpa-OH (3S)-3-Amino-4-(4'-benzoylpheny1)-butyric acid H-83-HOctG-OH (3S)-3-Amino-undecanoic acid H-133-HNIe-OH (3S)-3-Amino-heptanoic acid H-133-HTic-OH (3S)-1,2,3,4-Tetrahydroisoquinoline-3-yl-acetic acid H-83-HTiq-OH (1S)-1 ,2,3,4-Tetrahydroisoquinoline-1-acetic acid H-f33-HOic-OH (2S, 3aS, 7aS)-1-Octahydro-1H-indole-2-yl-acetic acid H483-H4AmPyrr1-0H (2S, 4S)-4-Amino-pyrrolidine-2-acetic acid H-83-H4AmPyrr2-0H (2S, 4R)-4-Amino-pyrrolidine-2-acetic acid H-83-H4PhePyrr1-0H (2S, 4R)-4-Phenyl-pyrrolidine-2-acetic acid H-83-H4PhePyrr2-0H (2S, 4S)-4-Phenyl-pyrrolidine-2-acetic acid H-133-H5PhePyrrl-OH (2S, 5R)-5-Phenyl-pyrrolidine-2-acetic acid H-133-H5PhePyrr2-0H (2S, 5S)-5-Phenyl-pyrrolidine-2-acetic acid 1-1-83-H4Hyp1-0H (2S, 4S)-4-Hydroxy-pyrrolidine-2-acetic acid H133-H4Hyp2-0H (2S, 4R)-4-Hydroxy-pyrrolidine-2-acetic acid H-133-H4Mp1-0H (2R, 4S)-4-Mercapto-pyrrolidine-2-acetic acid H-133-H4Mp2-OH (2R, 4R)-4-Mercapto-pyrrolidine-2-acetic acid H-83-HPip-OH (2S)-Piperidine-2-acetic acid H-83-HPro-OH (2S)-Pyrrolidine-2-acetic acid Ahb 4-Amino-2-hydroxy butyric acid H-y4-DiHCit-OH (4S)-4-Amino-7-carbamidyl-heptanoic acid H-y4-DiHOrn-OH (4S)-4,7-Diamino-heptanoic acid H-y4-DiHtBuA-OH (4R)-4-Amino-6,6-dimethyl-heptanoic acid H-y4-DiHSar-OH N-Methyl-4-amino-butyric acid Code Chemical Name H-y4-DiHPen-OH (4R)-4-Amino-5-methy1-5-mercapto-hexanoic acid H-y4-DiHtBuG-OH (4R)-4-Amino-5,5-dimethyl-hexanoic acid H-y4-DiH4AmPhe-OH (4R)-4-Amino-5-(4'-aminophenyI)-pentanoic acid H-y4-DiH3AmPhe-OH (4R)-4-Amino-5-(3'-aminophenyI)-pentanoic acid H-y4-DiH2AmPhe-OH (4R)-4-Amino-5-(2'-aminophenyI)-pentanoic acid H-y4-DiHPhe(mC(NH2)=
(4R)-4-Amino-5-(3'-amidinopheny1)-pentanoic acid NH)-OH
H-y4-DiHPhe(pC(NH2)=
(4R)-4-Amino-5-(4'-amidinophenyI)-pentanoic acid NH)-OH
H-y4-DiHPhe(mNHC(NH2)=
(4R)-4-Amino-5-(3'-guanidino-phenyl)-pentanoic acid NH)-OH
H-y4-DiHPhe(pNHC(NH2)=
NH OH (4R)-4-Amino-5-(4'-guanidino-phenyl)-pentanoic acid )-H-y4-DiH2Pal-OH (4R)-4-Amino-5-(pyridine-4'-yI)-pentanoic acid H-y4-DiH4Pal-OH (4R)-4-Amino-5-(pyridine-4'-yI)-pentanoic acid H-y4-DiHPhg-OH (4R)-4-Amino-4-phenyl-butyric acid H-y4-DiHCha-OH (4R)-4-Amino-5-cyclohexyl-pentanoic acid H-y4-DiHC4a1-0H (4R)-4-Amino-5-cyclobutyl-pentanoic acid H-y4-D1HC5a1-0H (4R)-4-Amino-5-cyclopentyl-pentanoic acid H-y4-DiHNIe-OH (4S)-4-Amino-octanoic acid H-y4-DiH2Nal-OH (4S)-4-Amino-5-(2'-naphthyl)-pentanoic acid H-y4-DiH1Nal-OH (4S)-4-Amino-5-(1'-naphthyl)-pentanoic acid H-y4-DiH4CIPhe-OH (4R)-4-Amino-5-(4'-chlorophenyI)-pentanoic acid H-y4-DiH3CIPhe-OH (4R)-4-Amino-5-(3'-chlorophenyI)-pentanoic acid H-y4-DiH2C1Phe-OH (4R)-4-Amino-5-(2'-chlorophenyI)-pentanoic acid H-y4-DiH3,4C12Phe-OH (4R)-4-Amino-5-(3',4'-dichloro-phenyl)-pentanoic acid H-y4-DiH4FPhe-OH (4R)-4-Amino-5-(4'-fluoropheny1)-pentanoic acid H-y4-DiH3FPhe-OH (4R)-4-Amino-5-(3'-fluorophenyI)-pentanoic acid H-y4-DiH2FPhe-OH (4R)-4-Amino-5-(2'-fluoropheny1)-pentanoic acid H-y4-DiHThi-OH (4R)-4-Amino-5-(2'-thieny1)-pentanoic acid H-y4-DiHTza-OH (4R)-4-Amino-5-(2'-thiazolyI)-pentanoic acid H-y4-D1HMso-OH (4R)-4-Amino-5-methylsulfoxyl-pentanoic acid H-y4-DiHAcLys-OH (4S)-8-Acetylamino-4-amino-ocatanoic acid Code Chemical Name H-y4-DiHDpr-OH (4R)-4,5-diamino-pentanoic acid H-y4-DiHA2Bu-OH (4R)-4,5-Diamino-hexanoic acid H-y4-DiHDbu-OH (4R)-4,5-Diamion-hexanoic acid H-y4-DiHAib-OH 3-Amino-3,3-dimethyl propionic acid H-y4-D1HCyp-OH (1'-Amino-cyclopentane-l'-y1)-3-propionic acid H-y4-DiHY(Bz1)-OH (4R)-4-Amino-5-(4'-benzyloxypheny1)-pentanoic acid (4R)-4-Amino-5-(1'-benzylimidazole-4'-y1)-pentanoic H-y4-DiHH(BzI)-OH
acid H-y4-DiHBip-OH (4R)-4-Amino-5-biphenylyl-pentanoic acid H-y4-D1HS(Bz1)-OH (4S)-4-Amino-5-(benzyloxy)-pentanoic acid H-y4-D1HT(Bz1)-OH (4R, 5R)-4-Amino-5-benzyloxy-hexanoic acid H-y4-DiHalloT-OH (4R, 5S)-4-Amino-5-hydroxy-hexanoic acid H-y4-DiHLeu30H-OH (4R, 5R)-4-Amino-5-hydroxy-6-methyl-heptanoic acid H-y4-DiHhAla-OH (4S)-4-Amino-hexanoic acid H-y4-DiHhArg-OH (4S)-4-Amino-8-guanidino-octanoic acid H-y4-DiHhCys-OH (4R)-Amino-6-mercapto-hexanoic acid H-y4-DiHhGlu-OH (4S)-4-Amino-ocatanedioic acid H-y4-D1HhGln-OH (4S)-4-Amino-7-carbamoyl-heptanoic acid H-y4-DiHhHis-OH (48)-4-Amino-6-(imidazole-4'-y1)-hexanoic acid H-y4-DiHhIle-OH (48, 6S)-4-Amino-6-methyl-octanoic acid H-y4-DiHhLeu-OH (4S)-4-Amino-7-methyl-ocatanoic acid H-y4-DiHhNle-OH (4S)-4-Amino-nonanoic acid H-y4-DiHhLys-OH (4S)-4,9-Diamino-nonanoic acid H-y4-DiHhMet-OH (4R)-4-Amino-7-methylthioheptanoic acid H-y4-DiHhPhe-OH (4S)-4-Amino-6-phenyl-hexanoic acid H-y4-DiHhSer-OH (4R)-4-Amino-6-hydroxy-hexanoic acid H-y4-DiHhThr-OH (4R, 6R)-4-Amino-6-hydroxy-heptanoic acid H-y4-DiHhTrp-OH (4S)-4-Amino-6-(indo1-3'-y1)-hexanoi cacid H-y4-DiHhTyr-OH (4S)-4-Amino-6-(4'-hydroxypheny1)-hexanoic acid H-y4-DiHhCha-OH (4R)-4-Amino-5-cyclohexyl-pentanoic acid H-y4-DihBpa-OH (4R)-4-Amino-5-(4'-benzoylpheny1)-pentanoic acid H-y4-DiHOctG-OH (4S)-4-Amino-dodecanoic acid H-y4-D1HMe-OH (4S)-4-Amino-octanoic acid Code Chemical Name (3R)-1',2',3',4'-Tetrahydroisoquinoline-3'-y1-3-propionic H-y4-DiHTic-OH
acid (1 'R)-1 ',2',3',4'-Tetrahydroisoquinoline-1 '-y1-3-propionic H-y4-D1HTiq-OH
acid (2'S, 3'aS, 7'aS)-1'-Octahydro-1H-indole-2'-y1-3-H-y4-DiHOic-OH
propionic acid H-y4-DiH4AmPyrr1-0H (2'R, 4'S)-4'-Amino-pyrrolidine-2'-y1-3-propionic acid H-y4-DiH4AmPyrr2-0H (2'R, 4'R)-4'-Amino-pyrrolidine-2'-y1-3-propionic acid H-y4-DiH4PhePyrr1-0H (2'R, 4'R)-4'-Phenyl-pyrrolidine-2'-y1-3-propionic acid H-y4-DiH4PhePyrr2-0H (2'R, 4'S)-4'-Phenyl-pyrrolidine-2'-y1-3-propionic acid H-y4-DiH5PhePyrr1-0H (2'S, 5'R)-5'-Phenyl-pyrrolidine-2'-y1-3-propionic acid H-y4-DiH5PhePyrr2-0H (2'S, 5'S)-5'-Phenyl-pyrrolidine-2'-y1-3-propionic acid H-y4-D11-14Hyp1-0H (2'R, 4'S)-4'-Hydroxy-pyrrolidine-2'-y1-2-propionic acid H-y4-DiH4Hyp2-0H (2'R, 4'R)-4'-Hydroxy-pyrrolidine-2'-y1-3-propionic acid H-y4-DiH4Mp1-OH (2'R, 4'S)-4'-Mercapto-pyrrolidine-2'-y1-3-propionic acid H-y4-DiH4Mp2-0H (2'R, 4'R)-4'-Mercapto-pyrrolidine-2'-y1-3-propionic acid H-y4-DiHPip-OH (2'S)-Piperidine-2'-y1-3-propionic acid H-y4-DiHPro-OH (2'S)-Pyrrolidine-2'-y1-3-propionic acid (AEt)G N-(2-Aminoethyl)glycine (APr)G N-(3-Amino-n-propyl)glycine (ABu)G N-(4-Amino-n-butyl)glycine (APe)G N-(5-Amino-n-pentyl)glycine (GuEt)G N-(2-Guanidinoethyl)glycine (GuPr)G N-(3-Guanidino-n-propyl)glycine (GuBu)G N-(4-Guanidino-n-butyl)glycine (GuPe)G N-(5-Guanidino-n-pentyl)glycine (PEG3-NH2)G N4H2N-(CH2)3-(OCH2-CH2)2-0(CH2)31glycine (Me)G N-Methylglycine (Et)G N-Ethylglycine (Bu)G N-Butylglycine (Pe)G N-Pentylglycine (1p)G N-Isopropylglycine (2MePr)G N-(2-Methylpropyl)glycine (3MeBu)G N-(3-Methylbutyl)glycine Code Chemical Name (1MePr)G (1S)-N-(1-Methylpropyl)glycine (2MeBu)G (2S)-N-(2-Methylbutyl)glycine (MthEt)G N-(Methylthioethyl)glycine (MthPr)G N-(Methylthiopropyl)glycine (Ben)G N-(Benzyl)glycine (PhEt)G N-(2-Phenylethyl)glycine (HphMe)G N-([4'-hydroxyphenylynethyl)glycine (HphEt)G N-(2[4'-hydroxyphenyliethyl)glycine (ImMe)G N-(lmidazol-5-yl-methyl)glycine (ImEt)G N-(2-(lmidazol-5'-yl)ethyl)glycine (InMe)G N-(lndo1-2-yl-methyl)glycine (1nEt)G N-(2-(Indo1-2'-yl)ethyl)glycine (CboMe)G N-(Carboxymethyl)glycine (CboEt)G N-(2-Carboxyethyl)glycine (CboPr)G N-(3-Carboxypropyl)glycine (CbaMe)G N-(Carbamoylmethyl)glycine (CbaEt)G N-(2-Carbamoylethyl)glycine (CbaPr)G N-(3-Carbamoylpropyl)glycine (HyEt)G N-(2-Hydroxyethyl)glycine (HyPr)G (2R)-N-(2-Hydroxypropyl)glycine (Mcet)G N-(2-Mercaptoethyl)glycine Nip (S)-Nipecotic acid/ (S)-3-Piperidinecarboxylic acid !Nip lsonipecotic acid/ 4-Piperidinecarboxylic acid PCA (S)-2-Piperazinecarboxylic acid (S)betaPro (S)-6-Proline/ (S)-Pyrrolidine-3-carboxylic acid In a Specific Embodiment of this invention, the macrocycles of formula I are selected from the following list (Table 12).
Table 12: IUPAC Names of the Examples (continued on the following pages) Example IUPAC Name benzyl N-[(12R,16S,18S)-16-[(tert-butoxycarbonyl)amino]-8,13-dioxo-20-Ex.1 oxa-9,14-diazatetracyclo[19.3.1.02,7.014,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-ylicarbamate tert-butyl N-[(12R,16S,18S)-12-amino-8,13-dioxo-20-oxa-9,14-Ex.2 diazatetracyclo[1 9.3.1.02,7.014,18]pentacosa-1(25),2,4,6,21,23-hexaen-16-yl]carbamate benzyl N-[(12R,16S,18S)-16-amino-8,13-dioxo-20-oxa-9,14-Ex.3 diazatetracyclo[19.3.1.02,7.014,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-ylicarbamate tert-butyl N-[(12R,16S,18S)-12-{[2-(1-naphthyl)acetyl]amino}-8,13-dioxo-Ex.4 20-oxa-9,14-diazatetracyclo[19.3.1.02,7.014,18]pentacosa-1(25),2,4,6,21,23-hexaen-16-yl]carbamate N-[(12R,16S,18S)-16-amino-8,13-dioxo-20-oxa-9,14-Ex.5 diazatetracyclo[19.3.1.02,7.014,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-y1]-2-(1-naphthypacetamide methyl N-[(12R,16S,18S)-12-{[2-(1-naphthypacetyllaminol-8,13-dioxo-20-Ex.6 oxa-9,14-diazatetracyclo[19.3.1.02,7.014,18]pentacosa-1(25),2,4,6,21,23-hexaen-16-ylicarbamate N-[(12R,16S,18S)-8,13-dioxo-16-{[2-(1-pyrrolidinyl)acetyl]amino20-oxa-Ex.7 9,14-diazatetracyclo[19.3.1.02,7.014,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-y1]-2-(1-naphthypacetamide N-[(12R,16S,18S)-16-(dimethylamino)-8,13-dioxo-20-oxa-9,14-Ex.8 diazatetracyclo[19.3.1.02,7.014,9pentacosa-1(25),2,4,6,21,23-hexaen-

12-y1]-2-(1-naphthyl)acetamide (12R,16S,18S)-12,16-diamino-20-oxa-9,14-Ex.9 diazatetracyclo[1 9.3.1.02,7.014,18]pentacosa-1(25),2,4,6,21,23-hexaene-8,13-dione benzyl N-[(12R,16S,18S)-16-{[2-(2-naphthyl)acetyl]amino}-8,13-dioxo-20-Ex.10 oxa-9,14-diazatetracyclo[19.3.1.02,7.014,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-yl]carbamate N-[(12R,16S,18S)-12-amino-8,13-dioxo-20-oxa-9,14-Ex.11 diazatetracyclo[1 9.3.1.02,7.014,18]pentacosa-1(25),2,4,6,21,23-hexaen-16-y1]-2-(2-naphthypacetamide 2-(dimethylamino)-N-[(12R,16S,18S)-16-{[2-(2-naphthyl)acetyljamino)-Ex.12 8,13-dioxo-20-oxa-9,14-diazatetracyclo[19.3.1.02,7.014,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-yl]acetamide 3-methyl-N-[(12R,16S,18S)-16-{[2-(2-naphthyl)acetyliaminol-8,13-dioxo-Ex.13 20-oxa-9,14-diazatetracyclo[19.3.1.027.014,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-ylibutanamide benzyl N-[(12R,16S,18S)-8,13-dioxo-16-[(phenoxycarbonypamino]-20-Ex.14 oxa-9,14-diazatetracyclo[19.3.1.02,7.014,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-yl]carbamate benzyl N-[(10S,12S,16S)-12-[(tert-butoxycarbonyl)amino]-20-methyl-Ex.15 15,21-dioxo-8-oxa-14,20-d iazatetracyclo[20.3.1.02,7.010,14]hexacosa-1(26),2,4,6,22,24-hexaen-16-yl]carbamate tert-butyl N-[(10S,12S,16S)-16-amino-20-methy1-15,21-dioxo-8-oxa-14,20-Ex.16 d iazatetracyclo[20.3.1.02,7.01 ,14]hexacosa-1(26),2,4,6,22,24-hexaen-12-yl]carbamate benzyl N-[(10S,12S,16S)-12-amino-20-methy1-15,21-dioxo-8-oxa-14,20-Ex.17 diazatetracyclo[20.3.1.02,7.010,14] hexacosa-1(26),2,4,6,22,24-hexaen-16-yl]carbamate benzyl N-[(10S,12S,16S)-20-methy1-12-{[2-(2-naphthyl)acetyl]amino}-Ex.18 15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.02,7.010,14]hexacosa-1(26),2,4,6,22,24-hexaen-16-ylicarbamate N-[(10S,12S,16S)-16-amino-20-methy1-15,21-dioxo-8-oxa-14,20-Ex.19 diazatetracyclo[20.3.1.027.010,14]hexacosa-1(26),2,4,6,22,24-hexaen-y11-2-(2-naphthyl)acetamide 2-(dimethylamino)-N-[(10S,12S,16S)-20-methy1-12-{[2-(2-naphthypacetyl]aminol-15,21-dioxo-8-oxa-14,20-Ex.20 diazatetracyclo[20.3.1.02,7.010,14]hexacosa-1(26),2,4,6,22,24-hexaen-16-yflacetamide N-[(10S,12S,165)-16-[(cyclopropylsulfonyl)amino]-20-methy1-15,21-dioxo-Ex.21 8-oxa-14,20-diazatetracyclo[20.3.1.02,7.010,14]hexacosa-1(26),2,4,6,22,24-hexaen-12-y1]-2-(2-naphthyl)acetamide N-[(10S,12S,16S)-20-methy1-16-{[(methylamino)carbonyl]amino)-15,21-Ex.22 dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.02,7.010,14]hexacosa-1(26),2,4,6,22,24-hexaen-12-y1]-2-(2-naphthypacetamide 2-methoxy-N-[(10S,12S,16S)-20-methy1-12-{[2-(2-naphthyl)acetyl]amino)-Ex.23 15,21-d ioxo-8-oxa-14 ,20-d iazatetracyclo[20.3.1.027.010,14]hexacosa-1(26),2,4,6,22,24-hexaen-16-yl]acetamide 3-methyl-N-[(10S,12S,16S)-20-methy1-12-{[2-(2-naphthypacetyl]amino)-Ex.24 15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.02,7.010,14Thexacosa-1(26),2,4,6,22,24-hexaen-16-yl]butanamide N-[(10S,12S,16S)-20-methy1-15,21-dioxo-16-[(2-phenylacetypamino]-8-Ex.25 oxa-14,20-diazatetracyclo[20.3.1.02,7.010,14Thexacosa-1(26),2,4,6,22,24-hexaen-12-y11-2-(2-naphthypacetamide N-[(10S,12S,16S)-20-methy1-12-{[2-(2-naphthyl)acetyl]amino)-15,21-Ex.26 dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.027.010,14Thexacosa-1(26),2,4,6,22,24-hexaen-16-yl]benzamide N-[(10S,12S,16S)-20-methy1-12-{[2-(2-naphthyl)acetyliamino}-15,21-Ex.27 dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.027.010,14]hexacosa-1(26),2,4,6,22,24-hexaen-16-yl]butanamide N-[(10S,12S,16S)-20-methy1-12-{[2-(2-naphthyl)acetyliamino}-15,21-Ex.28 dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.02,7.010,14]hexacosa-1(26),2,4,6,22,24-hexaen-16-ylipentanamide 2-{[(10S,12S,16S)-16-{[2-(dimethylamino)acetyl]amino}-20-methyl-15,21-Ex.29 dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.02,7.010,14]hexacosa-1(26),2,4,6,22,24-hexaen-12-yl]amino}acetic acid 2-(dimethylamino)-N-[(10S,12S,16S)-20-methy1-12-{Rmethylamino)carbothioyllamino}-15,21-dioxo-8-oxa-14,20-Ex.30 diazatetracyclo[20.3.1.02,7.010,11hexacosa-1(26),2,4,6,22,24-hexaen-16-yliacetamide 2-(dimethylamino)-N-[(10S,12S,16S)-20-methy1-15,21-dioxo-12-[(2-sulfanylacetyl)amino]-8-oxa-14,20-Ex.31 diazatetracyclo[20.3.1.02,7.010,14Thexacosa-1(26),2,4,6,22,24-hexaen-16-yl]acetamide 2-(dimethylamino)-N-[(10S,12S,16S)-20-methy1-15,21-dioxo-12-{[2-(tritylsulfanypacetyl]amino}-8-oxa-14,20-Ex.32 diazatetracyclo[20.3.1.027.010,14]hexacosa-1(26),2,4,6,22,24-hexaen-16-yl]acetamide 2-(dimethylamino)-N-R1 OS,12S,16S)-20-methy1-12-{[(methylamino)carbonyl]amino}-15,21-dioxo-8-oxa-14,20-Ex.33 diazatetracyclo[20.3.1.027.010,11hexacosa-1(26),2,4,6,22,24-hexaen-16-yllacetamide 2-(dimethylarnino)-N-R1 OS,12S,16S)-12-({[3-(dimethylamino)anilino]carbonyllamino)-20-methyl-15,21-dioxo-8-oxa-Ex.34 14,20-d iazatetracyclo[20.3.1.02,7.010,14]hexacosa-1(26),2,4,6,22,24-hexaen-16-yl]acetamide 2-(dimethylamino)-N-[(10S,12S,16S)-20-methy1-12-{[(2-naphthylamino)carbonyllamino)-15,21-dioxo-8-oxa-14,20-Ex.35 diazatetracyclo[20.3.1.02,7.010,14]hexacosa-1(26),2,4,6,22,24-hexaen-16-yl]acetamide 2-(dimethylamino)-N-[(10S,12S,16S)-20-methy1-12-[(methylsulfonyl)amino]-15,21-dioxo-8-oxa-14,20-Ex.36 diazatetracyclo[20.3.1.02,7.010o4]hexacosa-1(26),2,4,6,22,24-hexaen-16-ynacetamide N-[(105,12S,16S)-12-[(benzylsulfonyl)amino]-20-methy1-15,21 -dioxo-8-Ex.37 oxa-14,20-diazatetracyclo[20.3.1.02,7.010,14jhexacosa-1(26),2,4,6,22,24-hexaen-16-y1]-2-(dimethylamino)acetamide tert-butyl N-[(10S,12S,16S)-16-{[2-(dimethylamino)acetyl]amino}-20-methyl-15,21-dioxo-8-oxa-14,20-Ex.38 diazatetracyclo[20.3.1.02,7.010,14]hexacosa-1(26),2,4,6,22,24-hexaen-12-yl]carbamate N-[(10S,12S,16S)-12-amino-20-methy1-15,21-dioxo-8-oxa-14,20-Ex.39 diazatetracyclo[20.3.1.02,7.010,14]hexacosa-1(26),2,4,6,22,24-hexaen-y1]-2-(dimethylamino)acetamide ethyl 2-{[(10S,12S,16S)-16-{[2-(dimethylamino)acetyl]amino)-20-methyl-Ex.40 15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.02,7.010,14]hexacosa-1(26),2,4,6,22,24-hexaen-12-yaaminolacetate benzyl (10R,15S)-4-methoxy-10,16-dimethy1-12,17-dioxo-8-oxa-11,16-Ex.41 diazatricyclo[16.3.1.02,7]docosa-1(22),2,4,6,18,20-hexaene-15-carboxylate (10R,15S)-4-methoxy-10,16-dimethy1-12,17-dioxo-8-oxa-11,16-Ex.42 diazatricyclo[16.3.1.02,7]docosa-1(22),2,4,6,18,20-hexaene-15-carboxylic acid (10R,15S)-4-methoxy-10,16-dimethy1-12,17-dioxo-8-oxa-11,16-Ex.43 diazatricyclo[16.3.1.02,7]docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide _ _ (10R,15S)-4-methoxy-N,10,16-trimethy1-12,17-dioxo-8-oxa-11,16-Ex.44 diazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide (10R,15S)-4-methoxy-10,16-dimethy1-12,17-dioxo-N-pheny1-8-oxa-11,16-Ex.45 diazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide (10R,15S)-4-methoxy-10,16-dimethy1-15-(1-pyrrolidinylcarbony1)-8-oxa-Ex.46 11,16-diazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaene-12,17-dione (10R,15S)-N42-(dimethylamino)ethy11-4-methoxy-10,16-dimethyl-12,17-Ex.47 dioxo-8-oxa-11,16-diazatricyclo[1 6.3.1.021docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide tert-butyl N13-({[(10R,15S)-4-methoxy-10,16-dimethy1-12,17-dioxo-8-oxa-Ex.48 11,16-d iazatricycl o[16.3.1.021docosa-1(22),2,4,6,18,20-hexaen-15-yl]carbonyllamino)propyl]carbamate (10R,15S)-N-(3-aminopropy1)-4-methoxy-10,16-dimethy1-12,17-dioxo-8-Ex.49 oxa-11,16-diazatricyclo[1 6.3.1.021docosa-1(22),2,4,6,18,20-hexaene-carboxamide (10 R,15S)-4-methoxy-10,16-dimethy1-12,17-dioxo-N-(3-pyrid inylmethyl)-8-Ex.50 oxa-11,16-d iazatricyclorl 6.3.1.021docosa-1(22),2,4,6,18,20-hexaene-carboxamide (10R,15S)-4-methoxy-N-(2-methoxyethyl)-10,16-dimethy1-12,17-dioxo-8-Ex.51 oxa-11,16-diazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaene-carboxamide (10 R,15S)-N-cyclopropy1-4-methoxy-10,16-di methy1-12,17-dioxo-8-oxa-Ex.52 11,16-d iazatricycl o[16.3.1.02,1docosa-1(22),2,4,6,18,20-hexaene-15-carboxamid e (10R,15S)-4-methoxy-10,16-dimethy1-12,17-dioxo-N-(2,2,2-trifluoroethyl)-Ex.53 8-oxa-11,16-diazatricyclo[16.3.1.02,1docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide (10R,15S)-N-isobuty1-4-methoxy-10,16-dimethy1-12,17-dioxo-8-oxa-11,16-Ex.54 diazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide (10 R,15S)-N-(2-hydroxyethyl)-4-methoxy-10,16-dimethy1-12,17-dioxo-8-Ex.55 oxa-11,16-diazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide tert-butyl 2-({[(10R,15S)-4-methoxy-10,16-dimethy1-12,17-dioxo-8-oxa-Ex.56 11,16-diazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaen-15-ylIcarbonyllamino)acetate 2-({ [(10R,15S)-4-methoxy-10,16-dimethy1-12,17-dioxo-8-oxa-11,16-Ex.57 diazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaen-15-yl]carbonyllamino)acetic acid (10 R,15S)-4-methoxy-10,16-d imethy1-12,17-dioxo-N-[(1S)-1-phenylethy1]-Ex.58 8-oxa-11,16-diazatricyclo[1 6.3.1.02,1docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide (10R,15S)-N42-(dimethylamino)ethy1]-4-methoxy-N,10,16-trimethy1-12,17-Ex.59 dioxo-8-oxa-11,16-diazatricyclo[1 6.3.1.021docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide (10R,15S)-4-methoxy-10,16-dimethyl-N-(1-naphthylmethyl)-12,17-dioxo-Ex.60 8-oxa-11,16-diazatricyclo[1 6.3.1.021docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide (10R,15S)-4-methoxy-10,16-dimethyl-N-(2-naphthylmethyl)-12,17-dioxo-Ex.61 8-oxa-11,16-diazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide (10 R,15S)-15-(hydroxymethyl)-4-methoxy-10,16-d imethy1-8-oxa-11,16-Ex.62 diazatricyclo[16.3.1.027]docosa-1(22),2,4,6,18,20-hexaene-12,17-dione (10 R,15S)-4-methoxy-10,16-d imethy1-15-[(3-pyridinyloxy)methyl]-8-oxa-Ex.63 11,16-diazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaene-12,17-dione (10R,15S)-15-(azidomethyl)-4-methoxy-10,16-dimethy1-8-oxa-11,16-Ex.64 diazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaene-12,17-dione (10R,15S)-15-(aminomethyl)-4-methoxy-10,16-dimethy1-8-oxa-11,16-Ex.65 diazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaene-12,17-dione N-{[(10R,15S)-4-methoxy-10,16-dimethy1-12,17-dioxo-8-oxa-11,16-Ex.66 diazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaen-15-yl]methy11-2-phenylacetamide [(10R,15S)-4-methoxy-10,16-dimethy1-12,17-dioxo-8-oxa-11,16-Ex.67 diazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaen-15-yl]methyl N-phenylcarbamate benzyl (9 S,14 S)-9,15-d imethyl-11 ,16-dioxo-7-oxa-10,15-Ex.68 diazatricyclop 5.3.1.12,61docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxylate (9S,14S)-9,15-dimethy1-11,16-dioxo-7-oxa-10,15-Ex.69 d iazatricyclo[15.3.1.12,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxylic acid (9S,14S)-N,9,15-trimethy1-11,16-dioxo-7-oxa-10,15-Ex.70 diazatricyclo[l 5.3.1.12,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide (9S,14S)-9,15-dimethy1-11,16-dioxo-7-oxa-10,15-Ex.71 diazatricyclo[15.3.1.129docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide (9S,14 S)-9,15-d imethy1-11,16-di oxo-N-pheny1-7-oxa-10,15-Ex.72 diazatricyclo[15.3.1.12,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide (9S,14S)-9,15-dimethy1-11,16-dioxo-N-phenethy1-7-oxa-10,15-Ex.73 diazatricyclo[15.3.1.12,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide (9S,14S)-9,15-dimethyl-N-(1-naphthylmethyl)-11,16-dioxo-7-oxa-10,15-Ex.74 diazatricyclo[15.3.1.12,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide (9S,14S)-9,15-dimethy1-11,16-dioxo-N-(3-pyridinylmethyl)-7-oxa-10,15-Ex.75 diazatricyclo[15.3.1.12,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide (9 S,14S)-9,15-d imethy1-11 ,16-dioxo-N-[(1S)-1-phenylethy1]-7-oxa-10,15-Ex.76 diazatricyclo[15.3.1.12,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide (9 S,14 S)-N-(2-methoxyethyl)-9,15-d i methyl-11,16-d ioxo-7-oxa-10,15-Ex.77 diazatricyclo[15.3.1.126]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide (9 S,14 S)-9,15-d imethy1-11,16-dioxo-N-(2,2,2-trifluoroethyl)-7-oxa-10,15-Ex.78 diazatricyclo[15.3.1.121docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide (9 S,14 S)-N-cyclopropy1-9,15-d imethy1-11,16-di oxo-7-oxa-10,15-Ex.79 diazatricyclo[15.3.1.12,9docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide (9S,14S)-N-isobuty1-9,15-dimethy1-11,16-dioxo-7-oxa-10,15-Ex.80 diazatricyclo[15.3.1.12,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide (9 S,14 S)-N-(2-hydroxyethyl)-9,15-d i methyl-11,16-d ioxo-7-oxa-10,15-Ex.81 diazatricyclo[15.3.1.12,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide tert-butyl 2-({[(9S,14S)-9,15-dimethy1-11,16-dioxo-7-oxa-10,15-Ex.82 diazatricyclo[15.3.1.12,9docosa-1(21),2(22),3,5,17,19-hexaen-14-ylicarbonyl}amino)acetate 2-({[(9S,14S)-9,15-dimethy1-11,16-dioxo-7-oxa-10,15-Ex.83 diazatricyclo[15.3.1.12,6]docosa-1(21),2(22),3,5,17,19-hexaen-14-yl]carbonyl}amino)acetic acid (9 S,14 S)-N-[2-(d imethylamino)ethy1]-9 ,15-dimethy1-11,16-dioxo-7-oxa-Ex.84 10,15-diazatricyclo[15.3.1.126]docosa-1(21),2(22),3,5,17,19-hexaene-carboxamide (9S,14S)-9,15-dimethy1-11,16-dioxo-N43-(1-pyrrolidinyl)propy1]-7-oxa-Ex.85 10,15-d iazatricyclo[15.3.1.12,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide (9 S,14 S)-14-(1-azetanylcarbony1)-9,15-dimethy1-7-oxa-10,15-Ex.86 diazatricyclo[15.3.1.126]docosa-1(21),2(22),3,5,17,19-hexaene-11,16-dione (9S,14S)-9,15-dimethy1-14-(morpholinocarbony1)-7-oxa-10,15-Ex.87 diazatricyclo[15.3.1.12,6]docosa-1(21),2(22),3,5,17,19-hexaene-11,16-dione (9S,14S)-9,15-dimethyl-N-[(1-methy1-1H-imidazol-4-y1)methyl]-11,16-Ex.88 dioxo-7-oxa-10,15-diazatricyclo[l 5.3.1.12,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide (9S,14S)-9,15-dimethyl-N-(2-naphthylmethyl)-11,16-dioxo-7-oxa-10,15-Ex.89 diazatricyclo[15.3.1.126]clocosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide benzyl (9 S,11R)-11 -[(tert-butoxycarbonyl)amino]-14,20-dioxo-7-oxa-Ex.90 13,16,19,23-tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaene-16-carboxylate tert-butyl N-[(9S,11R)-14,20-dioxo-7-oxa-13,16,19,23-Ex.91 tetraazatetracyclo[19.3.1.126.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yllcarbamate benzyl (9 S,11R)-11-am ino-14,20-dioxo-7-oxa-13,16,19,23-Ex.92 tetraazatetracyclo[l 9.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaene-16-carboxylate (9S,11R)-11-amino-7-oxa-13,16,19,23-Ex.93 tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaene-14,20-dione tert-butyl N-[(9S,11R)-16-methy1-14,20-dioxo-7-oxa-13,16,19,23-Ex.94 tetraazatetracyclo[l 9.3.1.12,6.09,11hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]carbamate (9S,11R)-11-amino-16-methy1-7-oxa-13,16,19,23-Ex.95 tetraazatetracyclo[19.3.1.12,6.09,13Thexacosa-1(25),2(26),3,5,21,23-hexaene-14,20-dione N-[(9S,11R)-1 6-methy1-14,20-dioxo-7-oxa-13,16,19,23-Ex.96 tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-y1]-2-(2-naphthyl)acetam ide tert-butyl N-[(9S,11R)-16-(3-fluorobenzy1)-14,20-dioxo-7-oxa-13,16,19,23-Ex.97 tetraazatetracyclo[l 9.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]carbamate (9 S,11R)-11-amino-16-(3-fluorobenzy1)-7-oxa-13,16,19,23-Ex.98 tetraazatetracyclo[19.3.1.12,6.09,13Thexacosa-1(25),2(26),3,5,21,23-hexaene-14,20-dione N-[(9S,11R)-16-methy1-14,20-dioxo-7-oxa-13,16,19,23-Ex.99 tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]acetamide N-[(9S,11R)-16-(3-fluorobenzy1)-14,20-dioxo-7-oxa-13,16,19,23-Ex.100 tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yllacetamide N-[(9S,11R)-16-methy1-14,20-dioxo-7-oxa-13,16,19,23-Ex.101 tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-y1]-2-(1-naphthypacetamide N-[(9S,11R)-16-methy1-14,20-dioxo-7-oxa-13,16,19,23-Ex.102 tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-y1M-phenylurea N-[(9S,11R)-16-methy1-14,20-dioxo-7-oxa-13,16,19,23-Ex.103 tetraazatetracyclo[l 9.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-ylibenzenesulfonamide tert-butyl N-[(9S,11R)-1642-(dimethylamino)acety1]-14,20-dioxo-7-oxa-Ex.104 13,16,19,23-tetraazatetracyclor 9.3.1.12,6.09,13Thexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]carbamate (9S,11R)-11-amino-16-[2-(dimethylamino)acety1]-7-oxa-13,16,19,23-Ex.105 tetraazatetracyclo[l 9.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaene-14,20-dione N-[(9S,11R)-16-[2-(dimethylamino)acety1]-14,20-dioxo-7-oxa-13,16,19,23-Ex.106 tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-y1]-2-phenylacetamide N-[(9S,11R)-1 6-[2-(dimethylamino)acety1]-14,20-dioxo-7-oxa-13,16,19,23-Ex.107 tetraazatetracyclo[19.3.1.1 2,6.09,13Thexacosa-1(25),2(26),3,5,21,23-hexaen-11-ylicyclopropanesulfonamide N-[(9S,11R)-1612-(dimethylamino)acety1]-14,20-dioxo-7-oxa-13,16,19,23-Ex.108 tetraazatetracyclop 9.3.1.12,6.09,131hexacosa-1(25),2(26),3,5,21,23-hexaen-11-y11-N-methylurea tert-butyl N-[(9S,11R)-16-(cyclopropylsulfony1)-14,20-dioxo-7-oxa-Ex.109 13,16,19,23-tetraazatetracyclo[19.3.1.12,6.09,13Thexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]carbamate (9S,11R)-11-amino-16-(cyclopropylsulfony1)-7-oxa-13,16,19,23-Ex.110 tetraazatetracyclo[19.3.1.12,6.09,11hexacosa-1(25),2(26),3,5,21,23-hexaene-14,20-dione N-[(9S,11R)-16-(cyclopropylsulfony1)-14,20-dioxo-7-oxa-13,16,19,23-Ex.111 tetraazatetracyclo[ 1 9.3.1.126.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]benzamide tert-butyl N-[(9S,11R)-16-[(methylamino)carbonyl]-14,20-dioxo-7-oxa-Ex.112 13,16,19,23-tetraazatetracyclo[19.3.1.12,6.09,13Thexacosa-1(25),2(26),3,5,21,23-hexaen-11-ylicarbamate (9S,11R)-11-amino-N-methyl-14,20-dioxo-7-oxa-13,16,19,23-Ex.113 tetraazatetracyclo[19.3.1.12,6.09,13Thexacosa-1(25),2(26),3,5,21,23-hexaene-16-carboxamide (9S,11R)-11-[(3-fluorobenzoyl)amino]-N-methyl-14,20-dioxo-7-oxa-Ex.114 13,16,19,23-tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaene-16-carboxamide allyl N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-Ex.115 azatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carba mate (13S,16R)-13-amino-16-methyl-18-oxa-8-thia-15-Ex.116 azatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-14-one N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-Ex.117 azatricyclo[17.3.1.02,1tricosa-1(23),2,4,6,19,21-hexaen-13-y1]-2-(1-naphthypacetamide N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-Ex.118 azatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-y1]-2-(2-naphthyl)acetamide N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-Ex.119 azatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-y1]-2-(1-pyrrolidinyl)acetamide N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-Ex.120 azatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]nicotinamide 3-methyl-N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-Ex.121 azatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]butanamide methyl N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-Ex.122 azatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yllcarba mate N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-Ex.123 azatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-ylIcyclopropanesulfonamide N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-Ex.124 azatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]benzenesulfonamide N-methyl-Af-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-Ex.125 azatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yljurea N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-Ex.126 azatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-y1FN'-(3-pyridinyl)urea (13S,16R)-13-(isobutylamino)-16-methyl-18-oxa-8-thia-15-Ex.127 azatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-14-one (13S,16R)-13-(isopentylamino)-16-methyl-18-oxa-8-thia-15-Ex.128 azatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-14-one ally! N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8A6-thia-15-Ex.129 azatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate (13S,16R)-13-amino-16-methyl-18-oxa-8A6-thia-15-Ex.130 azatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaene-8,8,14-trione N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8A6-thia-15-Ex.131 azatricyclo[17.3.1.02,1tricosa-1(23),2,4,6,19,21-hexaen-13-y1]-2-(1-naphthyl)acetamide N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8A6-thia-15-Ex.132 azatricyclo[17.3.1.02,71tricosa-1(23),2,4,6,19,21-hexaen-13-y1]-2-(2-naphthypacetamide N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8A6-thia-15-Ex.133 azatricyclo[17.3.1.02,7]tricosa-1(23),2,4,6,19,21-hexaen-13-y1]-2-(1-pyrrolidinyl)acetamide N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8A6-thia-15-Ex.134 azatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-ylThicotinamide 3-methyl-N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8A6-thia-15-Ex.135 azatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]butanamide methyl N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8A6-thia-15-Ex.136 azatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8A6-thia-15-Ex.137 azatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-ylicyclopropanesulfonamide N-[(13S,16R)-16-methy1-8,8,14-trioxo-18-oxa-8A6-thia-15-Ex.138 azatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]benzenesulfonamide N-methyl-W-[(13S,16R)-16-methy1-8,8,14-trioxo-18-oxa-8A6-thia-15-Ex.139 azatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]urea N-[(13S,16R)-16-methy1-8,8,14-trioxo-18-oxa-8A6-thia-15-Ex.140 azatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-y1]-/V-(3-pyridinyOurea (13S,16R)-13-(isobutylamino)-16-methy1-18-oxa-8A6-thia-15-Ex.141 azatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaene-8,8,14-trione (13S,16R)-13-(isopentylamino)-16-methy1-18-oxa-8A6-thia-15-Ex.142 azatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaene-8,8,14-trione ally! N-[(10R,13S)-10-methy1-12-oxo-8-oxa-18-thia-11,21-Ex.143 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-ylicarbamate (10R,13S)-13-amino-10-methy1-8-oxa-18-thia-11,21-Ex.144 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-12-one (10R,13S)-13-(dimethylamino)-10-methy1-8-oxa-18-thia-11,21-Ex.145 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-12-one (10R,13S)-13-(isobutylamino)-10-methy1-8-oxa-18-thia-11,21-Ex.146 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-12-one (10R,13S)-13-[(3-fluorobenzyl)amino]-10-methy1-8-oxa-18-thia-11,21-Ex.147 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-12-one N-[(10R,13S)-10-methy1-12-oxo-8-oxa-18-thia-11,21-Ex.148 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yliacetamide 2-methoxy-N-[(10R,13S)-10-methy1-12-oxo-8-oxa-18-thia-11,21-Ex.149 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]acetamide 2-(dimethylamino)-N-[(10R,13S)-10-methy1-12-oxo-8-oxa-18-thia-11,21-Ex.150 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]acetamide N-[(10R,13S)-10-methy1-12-oxo-8-oxa-18-thia-11,21-Ex.151 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-ylinicotinamide 3-methyl-N-[(10R,13S)-10-methy1-12-oxo-8-oxa-18-thia-11,21-Ex.152 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yllbutanamide tert-butyl N-(3-{[(10R,13S)-10-methy1-12-oxo-8-oxa-18-thia-11,21-Ex.153 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]amino)-3-oxopropyl)carbamate 3-amino-N-R1OR,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21-Ex.154 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]propanamide N-[(10R,13S)-10-methy1-12-oxo-8-oxa-18-thia-11,21-Ex.155 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-y1]-2-(1-naphthypacetamide N-R1OR,13S)-10-methy1-12-oxo-8-oxa-18-thia-11,21-Ex.156 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-y1]-2-(2-naphthyl)acetamide 3,3,3-trifluoro-N-[(10R,13S)-10-methy1-12-oxo-8-oxa-18-thia-11,21-Ex.157 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]propanamide 3-fluoro-N-[(10R,13S)-10-methy1-12-oxo-8-oxa-18-thia-11,21-Ex.158 diazatricyclo[17.3.1.02,71tricosa-1(23),2,4,6,19,21-hexaen-13-yl]benzamide N-[(10R,13S)-10-methy1-12-oxo-8-oxa-18-thia-11,21-Ex.159 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-y1]-1V-(3-pyridinyOurea N-methyl-M-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21-Ex.160 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]urea tert-butyl 3-[({[(10R,13S)-10-methy1-12-oxo-8-oxa-18-thia-11,21-Ex.161 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]aminolcarbonyl)amino]propanoate 3-[({[(10R,13S)-10-methy1-12-oxo-8-oxa-18-thia-11,21-Ex.162 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-Aaminolcarbonyl)amino]propanoic acid N-[(10R,13S)-10-methy1-12-oxo-8-oxa-18-thia-11,21-Ex.163 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-Amethanesulfonamide N-[(10R,13S)-10-methy1-12-oxo-8-oxa-18-thia-11,21-Ex.164 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]cyclopropanesulfonamide N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21-Ex.165 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]benzenesulfonamide methyl N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21-Ex.166 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate 2-methoxyethyl N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21-Ex.167 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate ally' N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18A6-thia-11,21-Ex.168 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-ylicarbamate (10R,13S)-13-amino-10-methyl-8-oxa-18A6-thia-11,21-Ex.169 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaene-12,18,18-trione (10R,13S)-13-(dimethylamino)-10-methyl-8-oxa-18A6-thia-11,21-Ex.170 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaene-12,18,18-trione (10R,13S)-13-(isobutylamino)-10-methyl-8-oxa-18A6-thia-11,21-Ex.171 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaene-12,18,18-trione (10R,13S)-13-[(3-fluorobenzyl)amino]-10-methyl-8-oxa-18A6-thia-11,21-Ex.172 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaene-12,18,18-trione N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18A6-thia-11,21-Ex.173 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]acetamide 2-methoxy-N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18A6-thia-11,21-Ex.174 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yliacetamide 2-(d imethylamino)-N-[(10R,13 S)-10-methyl-12 ,18,18-trioxo-8-oxa-18A6-Ex.175 thia-11,21-diazatricyclo[17.3.1.02,7]tricosa-1(23),2,4,6,19,21-hexaen-

13-yl]acetamide N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18A6-thia-11,21-Ex.176 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]nicotinamide 3-methyl-N-R1OR,13S)-10-methyl-12,18,18-trioxo-8-oxa-18A6-thia-11,21-Ex.177 diazatricyclo[17.3.1.029tricosa-1(23),2,4,6,19,21-hexaen-13-yl]butanamide tert-butyl N-(3-{[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18A6-thia-Ex.178 11,21-d iazatricyclo[17.3.1.02,1tricosa-1(23),2,4 ,6,19,21-hexaen-13-yl]ami no}-3-oxopropyl)carbamate 3-amino-N-[(10R,13S)-10-methy1-12,18,18-trioxo-8-oxa-18A6-thia-11,21-Ex.179 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]propanamide N-[(10R,13S)-10-methy1-12,18,18-trioxo-8-oxa-18A6-thia-11,21-Ex.180 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-y1]-2-(1-naphthyl)acetamide N-[(10R,13S)-10-methy1-12,18,18-trioxo-8-oxa-18A6-thia-11,21-Ex.181 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-y1]-2-(2-naphthypacetamide 3,3,3-trifluoro-N-[(10R,13S)-10-methy1-12,18,18-trioxo-8-oxa-18A6-thia-Ex.182 11,21-d iazatricycl o[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]propanamide 3-fluoro-N-[(10R,13S)-10-methy1-12,18,18-trioxo-8-oxa-18A6-thia-11,21-Ex.183 diazatricyclo[17.3.1.02,1tricosa-1(23),2,4,6,19,21-hexaen-13-ylibenzamide N-[(10R,13S)-10-methy1-12,18,18-trioxo-8-oxa-18A6-thia-11,21-Ex.184 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-y1W-(3-pyridinyOurea N-methyl-W-R1OR,13S)-10-methyl-12,18,18-trioxo-8-oxa-18A6-thia-11,21-Ex.185 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yllurea tert-butyl 3-[({[(10R,13S)-10-methy1-12,18,18-trioxo-8-oxa-18A6-thia-11,21-Ex.186 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yllamino}carbonyl)amino]propanoate 3-[({[(10R,13S)-10-methy1-12,18,18-trioxo-8-oxa-18A6-thia-11,21-Ex.187 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yliaminolcarbonyl)amino]propanoic acid N-[(10R,13S)-10-methy1-12,18,18-trioxo-8-oxa-18A6-thia-11,21-Ex.188 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]methanesulfonamide N-[(10R,13S)-10-methy1-12,18,18-trioxo-8-oxa-18A6-thia-11,21-Ex.189 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]cyclopropanesulfonamide N-[(10R,13S)-10-methy1-12,18,18-trioxo-8-oxa-18A6-thia-11,21-Ex.190 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-Abenzenesulfonamide methyl N-[(10R,13S)-10-methy1-12,18,18-trioxo-8-oxa-18A6-thia-11,21-Ex.191 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate 2-methoxyethyl N-[(10R,13S)-10-methy1-12,18,18-trioxo-8-oxa-18A6-thia-Ex.192 11,21-diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate (9S,16S,19R)-16-benzy1-19,20-dimethy1-7-oxa-13,17,20,24-Ex.193a tetraazatetracyclo[20.3.1.12,6.09,13]heptacosa-1(26),2(27),3,5,22,24-hexaene-14,18,21-trione (9S,19S)-19-benzy1-20-methy1-7-oxa-13,17,20,24-Ex.193c tetraazatetracyclo[20.3.1.12n6.09,13]heptacosa-1(26),2(27),3,5,22,24-hexaene-14,18,21-trione (9S,19S)-19-benzy1-7-oxa-13,17,20,24-Ex.193d tetraazatetracyclo[20.3.1.12,6.09,13Theptacosa-1(26),2(27),3,5,22,24-hexaene-14,18,21-trione (9S,16R,19S)-19-benzy1-16,17,20-trimethy1-7-oxa-13,17,20,24-Ex.193e tetraazatetracyclo[20.3.1.12,6.09,13]heptacosa-1(26),2(27),3,5,22,24-hexaene-14,18,21-trione (9S,16R)-16,17,20-trimethy1-7-oxa-13,17,20,24-Ex.193f tetraazatetracyclo[20.3.1.12,6.09,13]heptacosa-1(26),2(27),3,5,22,24-hexaene-14,18,21-trione (9S,16R,19S)-19-benzy1-16,17-dimethy1-7-oxa-13,17,20,24-Ex.193g tetraazatetracyclo[20.3.1.12,6.09,13]heptacosa-1(26),2(27),3,5,22,24-hexaene-14,18,21-trione (9S,16S)-16-benzy1-21-methy1-7-oxa-13,17,21,25-Ex.193h tetraazatetracyclo[21.3.1.12,6.09µ13]octacosa-1(27),2(28),3,5,23,25-hexaene-14,18,22-trione 3-[(9S,16R,19S)-16,17,20-trimethy1-14,18,21-trioxo-7-oxa-13,17,20,24-Ex.194b tetraazatetracyclo[20.3.1.12,6.09,13]heptacosa-1(26),2(27),3,5,22,24-hexaen-19-yl]propanoic acid (9 S,16R,22S)-16,17,20,22,23-pentamethy1-7-oxa-13,17,20,23,27-Ex.195a pentaazatetracyclo[23.3.1.12,6.09,13]triaconta-1(29),2(30),3,5,25,27-hexaene-14,18,21,24-tetrone (9S,16R,22S)-16,17,22-trimethy1-7-oxa-13,17,20,23,27-Ex.195b pentaazatetracyclo[23.3.1.126.09,13]triaconta-1(29),2(30),3,5,25,27-hexaene-14,18,21,24-tetrone (9S,19R,22S)-16,19,20,22,23-pentamethy1-7-oxa-13,16,20,23,27-Ex.195e pentaazatetracyclo[23.3.1.12,6.09,13]triaconta-1(29),2(30),3,5,25,27-hexaene-14,17,21,24-tetrone (9S,18S,22R)-16,18,19,22,23-pentamethy1-7-oxa-13,16,19,23,27-Ex.195f pentaazatetracyclo[23.3.1.12,6.09,11triaconta-1(29),2(30),3,5,25,27-hexaene-14,17,20,24-tetrone (9S,18S,21R)-18-benzy1-21,22-dimethy1-7-oxa-13,16,19,22,26-Ex.195g pentaazatetracyclo[22.3.1.12,6.09,11nonacosa-1(28),2(29),3,5,24,26-hexaene-14,17,20,23-tetrone (9S,18S,21R)-18-benzy1-16,21-dimethy1-7-oxa-13,16,19,22,26-Ex.195h pentaazatetracyclo[22.3.1.12,6.09,131nonacosa-1(28),2(29),3,5,24,26-hexaene-14,17,20,23-tetrone (9S,18S,21R)-18-benzy1-16,21,22-trimethy1-7-oxa-13,16,19,22,26-Ex.195j pentaazatetracyclo[22.3.1.126.09,131nonacosa-1(28),2(29),3,5,24,26-hexaene-14,17,20,23-tetrone 3-[(9S,161?,19S,22S)-16,17,19,23-tetramethy1-14,18,21,24-tetraoxo-7-Ex.196c oxa-13,17,20,23,27-pentaazatetracyclo[23.3.1.12,6.09,13]triaconta-1(29),2(30),3,5,25,27-hexaen-22-yl]propanoic acid 3-[(9 S,15S,18R,21S)-18-benzy1-15 ,22-d 'methyl-14,17,20 ,23-tetraoxo-7-Ex.196i oxa-13,16,19,22,26-pentaazatetracyclo[22.3.1.12,6.09.131nonacosa-1(28),2(29),3,5,24,26-hexaen-21-yl]propanoic acid 3-[(9 S,15R,18S,21S)-18-benzy1-15,22-d imethy1-14,17,20,23-tetraoxo-7-Ex.196k oxa-13,16,19,22,26-pentaazatetracyclo[22.3.1.12,6.09,13]nonacosa-1(28),2(29),3,5,24,26-hexaen-21-yl]propanoic acid (9S,16R,19S,22R)-19-(4-aminobuty1)-16,17,22-trimethy1-7-oxa-Ex.197d 13,17,20,23,27-pentaazatetracyclo[23.3.1.12,6.09,19triaconta-1(29),2(30),3,5,25,27-hexaene-14,18,21,24-tetrone benzyl (10S,12S)-12-[(tert-butoxycarbonyl)amino]-15,21-dioxo-8-oxa-Ex.198 3,14,17,20-tetraazatetracyclo[20.2.2.02,7.010,14Thexacosa-1(24),2,4,6,22,25-hexaene-17-carboxylate benzyl (10S,12S)-12-amino-15,21-dioxo-8-oxa-3,14,17,20-Ex.199 tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaene-17-carboxylate -tert-butyl N-[(10S,12S)-15,21-dioxo-8-oxa-3,14,17,20-Ex.200 tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaen-12-yl]carbamate tert-butyl N-[(1 OS, I 2S)-17-methy1-15,21-dioxo-8-oxa-3,14,17,20-Ex.201 tetraazatetracyclo[20.2.2.02,7.01 ,14Thexacosa-1(24),2,4,6,22,25-hexaen-12-yl]carbamate (10S,12S)-12-amino-17-methy1-8-oxa-3,14,17,20-Ex.202 tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaene-15,21-dione N-[(10S,12S)-17-methy1-15,21-dioxo-8-oxa-3,14,17,20-Ex.203 tetraazatetracyclo[20.2.2.02,7.010,141hexacosa-1(24),2,4,6,22,25-hexaen-12-y1]-2-(1-naphthyl)acetamide 3-methyl-N-[(10S,12S)-17-methy1-15,21-dioxo-8-oxa-3,14,17,20-Ex.204 tetraazatetracyclo[20.2.2.02,7.010,14Thexacosa-1(24),2,4,6,22,25-hexaen-12-yl]butanamide N-[(10S,12S)-17-methy1-15,21-dioxo-8-oxa-3,14,17,20-Ex.205 tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaen-12-y1W-(3-pyridinyl)urea N-[(10S,12S)-17-methy1-15,21-dioxo-8-oxa-3,14,17,20-Ex.206 tetraazatetracyclo[20.2.2.02,7.010,14Thexacosa-1(24),2,4,6,22,25-hexaen-12-yl]benzenesulfonamide tert-butyl N-[(10S,12S)-1742-(dimethylamino)acety1]-15,21-dioxo-8-oxa-Ex.207 3,14,17,20-tetraazatetracyclo[20.2.2.027.010,14]hexacosa-1(24),2,4,6,22,25-hexaen-12-yl]carbamate (10S,12S)-12-amino-1712-(dimethylamino)acety1]-8-oxa-3,14,17,20-Ex.208 tetra azatetra cyclo[20.2.2.027.010,14Thexacosa-1(24),2,4,6,22,25-hexaene-15,21-dione N-[(10S,12S)-1712-(dimethylamino)acety1]-15,21-dioxo-8-oxa-3,14,17,20-Ex.209 tetraazatetracyclo[20.2.2.02,7.01 ,14]hexacosa-1(24),2,4,6,22,25-hexaen-12-y1]-2-phenylacetamide N-[(10S,12S)-1742-(dimethylamino)acety1]-15,21-dioxo-8-oxa-3,14,17,20-Ex.210 tetraazatetracyclo[20.2.2.02,7.01 ,14]hexacosa-1(24),2,4,6,22,25-hexaen-12-y1]-M-methylurea N-[(10S,12S)-1742-(dirnethylamino)acety1]-15,21-dioxo-8-oxa-3,14,17,20-Ex.211 tetraazatetracyclo[20.2.2.027.010,14]hexacosa-1(24),2,4,6,22,25-hexaen-12-yl]cyclopropanesulfonamide benzyl (10S,12S)-12-(acetylamino)-15,21-dioxo-8-oxa-3,14,17,20-Ex.212 tetraazatetracyclo[20.2.2.02,7.010,11hexacosa-1(24),2,4,6,22,25-hexaene-17-carboxylate N-[(10S,12S)-15,21-dioxo-8-oxa-3,14,17,20-Ex.213 tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaen-12-yl]acetamide N-[(10S,12S)-17-(3-fluorobenzy1)-15,21-dioxo-8-oxa-3,14,17,20-Ex.214 tetraazatetracyclo[20.2.2.02,7.010,141hexacosa-1(24),2,4,6,22,25-hexaen-12-ynacetamide N-[(105,12S)-15,21-dioxo-17-[2-(1-pyrrolidinypacety1]-8-oxa-3,14,17,20-Ex.215 tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaen-12-yllacetamide (10S,12S)-12-(acetylamino)-15,21-dioxo-N-pheny1-8-oxa-3,14,17,20-Ex.216 tetraazatetracyclo[20.2.2.02n7.010,14]hexacosa-1(24),2,4,6,22,25-hexaene-17-carboxamide N-[(105,125)-15,21-dioxo-17-(phenylsulfony1)-8-oxa-3,14,17,20-Ex.217 tetraazatetracyclo[20.2.2.02,7.010,14Thexacosa-1(24),2,4,6,22,25-hexaen-12-yl]acetamide 3-({[(10S,12S)-12-(acetylamino)-15,21-dioxo-8-oxa-3,14,17,20-Ex.218 tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaen-17-yl]carbonyllamino)propanoic acid tert-butyl 3-({[(10S,125)-12-(acetylamino)-15,21-dioxo-8-oxa-3,14,17,20-Ex.219 tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaen-17-yl]carbonyllamino)propanoate methyl (8S,17S,195)-17-[(tert-butoxycarbonyl)amino]-24-fluoro-6,14-Ex.220 dioxo-10,21-dioxa-4-thia-7,15-diazatetracyclo[20.3.1.12,5.015,19]heptacosa-1(26),2,5(27),12,22,24-hexaene-8-carboxylate methyl (8S,175,195)-17-[(tert-butoxycarbonyl)amino]-24-fluoro-6,14-Ex.221 dioxo-10,21-dioxa-4-thia-7,15-diazatetracyclo[20.3.1.12,5.015,19]heptacosa-1(26),2,5(27),22,24-pentaene-8-carboxylate methyl (8S,17S,19S)-17-amino-24-fluoro-6,14-dioxo-10,21-dioxa-4-thia-Ex.222 7,15-diazatetracyclo[20.3.1.125.015,19heptacosa-1(26),2,5(27),22,24-pentaene-8-carboxylate methyl (8S,17S,19S)-24-fluoro-6,14-dioxo-17-[(2-phenylacetyl)amino]-Ex.223 10,21-dioxa-4-thia-7,15-diazatetracyclo[20.3.1.12,5.015,19]heptacosa-1(26),2,5(27),22,24-pentaene-8-carboxylate (8S,17S,19S)-24-fluoro-6,14-dioxo-17-[(2-phenylacetyl)amino]-10,21-Ex.224 dioxa-4-thia-7,15-diazatetracyclo[20.3.1.125.015,19]heptacosa-1(26),2,5(27),22,24-pentaene-8-carboxylic add (8S,17S,19S)-24-fluoro-6,14-dioxo-17-[(2-phenylacetyl)amino]-10,21-Ex.225 dioxa-4-thia-7,15-diazatetracyclo[20.3.1.12,5.015,19]heptacosa-1(26),2,5(27),22,24-pentaene-8-carboxamide (8S,17S,19S)-24-fluoro-N-isobuty1-6,14-dioxo-17-[(2-phenylacetyl)amino]-Ex.226 10,21-dioxa-4-thia-7,15-diazatetracyclo[20.3.1.12,5.015,19]heptacosa-1(26),2,5(27),22,24-pentaene-8-carboxamide methyl (8S,12E,18S,20S)-18-Rtert-butoxycarbonyl)amino]-25-fluoro-6,15-Ex.227 dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1 .12,5.016,20]octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxylate (8S,12E,18S,20S)-18-[(tert-butoxycarbonyl)amino]-25-fluoro-6,15-dioxo-Ex.228 10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.12,5.01629octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxylic acid methyl (8S,12E, 18S,20S)-18-amino-25-fluoro-6,15-dioxo-10,22-dioxa-4-Ex.229 thia-7,16-diazatetracyclo[21.3.1.125.016,29octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxylate methyl (8S,12E, 18S,20S)-25-fluoro-1842-(2-naphthyl)acetyliamino-6,15-Ex.230 dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.12,5.016,29octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxylate tert-butyl N-[(8S,12E, 18S,20S)-25-fluoro-8-[(isobutylamino)carbonyI]-6,15-dioxo-10,22-dioxa-4-thia-7,16-Ex.231 diazatetracyclo[21.3.1.12,5.016,29octacosa-1(27),2,5(28),12,23,25-hexaen-18-ylicarbamate (8S,12E,18S,20S)-18-amino-25-fluoro-N-isobuty1-6,15-dioxo-10,22-dioxa-Ex.232 4-thia-7,16-diazatetracyclo[21.3.1.12,5.016,29octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxamide (8S,12E,18S,20S)-25-fluoro-N-isobuty1-6,15-dioxo-18-[(3-pyridinylcarbonyl)amino]-10,22-dioxa-4-thia-7,16-Ex.233 diazatetracyclo[21.3.1.12.5.016,29octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxamide tert-butyl N-[(8S,12E,18S,20S)-8-(anilinocarbony1)-25-fluoro-6,15-dioxo-Ex.234 10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 25. 016,29octacosa-1(27),2,5(28),12,23,25-hexaen-18-ylicarbamate (8S,12E,18S,20S)-18-amino-25-fluoro-6,15-dioxo-N-pheny1-10,22-dioxa-Ex.235 4-thia-7,16-diazatetracyclo[21.3.1.12,5.016,29octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxamide methyl (8S,12E,18S,20S)-25-fluoro-6,15-dioxo-18-[(2-phenylacetyl)amino]-10,22-dioxa-4-thia-7,16-Ex.236 diazatetracyclo[21.3.1.12,5.016,29octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxylate (8S,12E,18S,20S)-25-fluoro-6,15-dioxo-18-[(2-phenylacetyl)amino]-10,22-Ex.237 dioxa-4-thia-7,16-diazatetracyclo[21.3.1.12,5.016,29octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxylic acid methyl (8S,12E,18S,20S)-18-[(3-chlorobenzoyl)amino]-25-fluoro-6,15-Ex.238 dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.125.016,29octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxylate (8S,12E,18S,20S)-18-[(3-chlorobenzoyl)amino]-25-fluoro-6,15-dioxo-Ex.239 10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.12,5.016,29octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxylic acid (8S,12E,18S,20S)-25-fluoro-N-isobuty1-18-{[2-(2-naphthyl)acetyl]amino)-6,15-dioxo-10,22-dioxa-4-thia-7,16-Ex.240 diazatetracyclo[21.3.1.12,5.016,29octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxamide (8S,12E,18S,20S)-25-fluoro-18-{[2-(2-naphthyl)acetyl]amino)-6,15-dioxo-Ex.241 10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.12,5.016,201octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxylic acid methyl (8S,18S,20S)-18-[(tert-butoxycarbonyl)amino]-25-fluoro-6,15-Ex.242 dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.12,5.016,29octacosa-1(27),2,5(28),23,25-pentaene-8-carboxylate (8 S,18S,20 S)-18-[(tert-butoxycarbonyl)amino]-25-fluoro-6,15-dioxo-10,22-Ex.243 dioxa-4-thia-7,16-diazatetracyclo[21.3.1.12,5.016,29octacosa-1(27),2,5(28),23,25-pentaene-8-carboxylic acid methyl (8S,18S,20S)-18-amino-25-fluoro-6,15-dioxo-10,22-dioxa-4-thia-Ex.244 7,16-di azatetracyclo[21.3.1.125.016,29octacosa-1(27),2,5(28),23,25-pentaene-8-carboxylate methyl (8S,18S,20S)-25-fluoro-18-{[2-(2-naphthypacetyllamino}-6,15-Ex.245 dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.12,5.016,29octacosa-1(27),2,5(28),23,25-pentaene-8-carboxylate tert-butyl N-[(8S,18S,20S)-8-(anilinocarbony1)-25-fluoro-6,15-dioxo-10,22-Ex.246 dioxa-4-thia-7,16-diazatetracyclo[21.3.1.12,5.016,20]octacosa-1(27),2,5(28),23,25-pentaen-18-ylicarbamate (8S,18S,20S)-18-amino-25-fluoro-6,15-dioxo-N-pheny1-10,22-dioxa-4-thia-Ex.247 7,16-diazatetracyclo[21.3.1.12,5.016,29octacosa-1(27),2,5(28),23,25-pentaene-8-carboxamide methyl (8S,18S,20S)-25-fluoro-6,15-dioxo-18-[(2-phenylacetypamino]-Ex.248 10,22-di oxa-4-thia-7,16-d iazatetracyclo[21.3.1.12,5.016,29octacosa-1(27),2,5(28),23,25-pentaene-8-carboxylate (8S,18S,20S)-18-[(3-chlorobenzoyl)amino]-25-fluoro-6,15-dioxo-10,22-Ex.249 dioxa-4-thia-7,16-diazatetracyclo[21.3.1.12,5.016,29octacosa-1(27),2,5(28),23,25-pentaene-8-carboxylic acid methyl (8S,18S,20S)-18-[(3-chlorobenzoyl)amino]-25-fluoro-6,15-dioxo-Ex.250 10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.12,5.016,29octacosa-1(27),2,5(28),23,25-pentaene-8-carboxylate (8S,18S,20S)-25-fluoro-6,15-dioxo-18-[(2-phenylacetyl)amino]-10,22-Ex.251 dioxa-4-thia-7,16-diazatetracyclo[21.3.1.12,5.016,20]octacosa-1(27),2,5(28),23,25-pentaene-8-carboxylic acid (8S,18S,20S)-25-fluoro-18-{[2-(2-naphthyl)acetyl]amino}-6,15-dioxo-Ex.252 10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.12,5.016,29octacosa-1(27),2,5(28),23,25-pentaene-8-carboxylic acid tert-butyl N-R8S,18S,20S)-25-fluoro-8-Risobutylamino)carbony1]-6,15-Ex.253 dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.12,5.016,29octacosa-1(27),2,5(28),23,25-pentaen-18-ylicarbamate (8S,18S,20S)-18-amino-25-fluoro-N-isobuty1-6,15-dioxo-10,22-dioxa-4-Ex.254 thia-7,16-diazatetracyclo[21.3.1.12,5.016,29octacosa-1(27),2,5(28),23,25-pentaene-8-carboxamide (8S,18S,20S)-25-fluoro-N-isobuty1-6,15-dioxo-18-[(3-pyridinylcarbonyl)amino]-10,22-dioxa-4-thia-7,16-Ex.255 diazatetracyclo[21.3.1.12,5.016,29octacosa-1(27),2,5(28),23,25-pentaene-8-carboxamide tert-butyl N-R8S,18S,20S)-8-[(4-chloroanilino)carbony1]-25-fluoro-6,15-Ex.256 dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.12,5.016,21octacosa-1(27),2,5(28),23,25-pentaen-18-yl]carbamate (8S,18S,20S)-18-amino-N-(4-chloropheny1)-25-fluoro-6,15-dioxo-10,22-Ex.257 dioxa-4-thia-7,16-diazatetracyclo[21.3.1.12,5.016,29octacosa-1(27),2,5(28),23,25-pentaene-8-carboxamide tert-butyl N-[(8S,18S,20S)-25-fluoro-6,15-dioxo-8-(3-tol uid inocarbony1)-Ex.258 10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.12,5.016,29octacosa-1(27),2,5(28),23,25-pentaen-18-yl]carbam ate (8S,18S,20S)-18-amino-25-fluoro-N-(3-methylpheny1)-6,15-dioxo-10,22-Ex.259 dioxa-4-thia-7,16-diazatetracyclo[21.3.1.12,5.016,29octacosa-1(27),2,5(28),23,25-pentaene-8-carboxamide tert-butyl N-[(8S,18S,20S)-8-Rbenzylamino)carbonyl]-25-fluoro-6,15-Ex.260 dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.12,5.016,29octacosa-1(27),2,5(28),23,25-pentaen-18-yl]carbamate (8S,18S,20S)-18-amino-N-benzy1-25-fluoro-6,15-dioxo-10,22-dioxa-4-thia-Ex.261 7,16-di azatetracyclo[21.3.1.12,5.016,29octacosa-1(27),2,5(28),23,25-pentaene-8-carboxamide benzyl N-[(9S,11S,15S)-11-[(4-bromobenzyl)oxy]-18,21-d 'methyl-14,19-Ex.262 dioxo-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-yl]carbamate (9S,11S,15S)-15-amino-11-hydroxy-18,21-dimethy1-7-oxa-3-thia-Ex.263 13,18,21,22-tetraazatetracyclo[18.2.1.02,6.09,19tricosa-1(22),2(6),4,20(23)-tetraene-14,19-dione (9S,11S,15S)-15-amino-11-(benzyloxy)-18,21-dimethy1-7-oxa-3-thia-Ex.264 13,18,21,22-tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraene-14,19-dione N-[(9S,11S,15S)-11-hydroxy-18,21-dimethy1-14,19-dioxo-7-oxa-3-thia-Ex.265 13,18,21,22-tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-y1]-2-(2-naphthyl)acetamide N-[(9S,11S,15S)-11-(benzyloxy)-18,21-dimethy1-14,19-dioxo-7-oxa-3-thia-Ex.266 13,18,21,22-tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-yliacetamide N-[(9S,11S,15S)-11-hydroxy-18,21-dimethy1-14,19-dioxo-7-oxa-3-thia-Ex.267 13,18,21,22-tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6) ,4,20(23)-tetraen-15-y1]-2-(1-naphthyl)acetamide N-[(9S,11S,15S)-11-hydroxy-18,21-dimethy1-14,19-dioxo-7-oxa-3-thia-Ex.268 13,18,21,22-tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20 (23)-tetraen-15-y1]-3-methylbutanam ide 3-fluoro-N-[(9S,11S,15S)-11-hydroxy-18,21-dimethy1-14,19-dioxo-7-oxa-3-Ex.269 thia-13,18,21,22-tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-yl]benzamide N-[(9S,11S,15S)-11-hydroxy-18,21-dimethy1-14,19-dioxo-7-oxa-3-thia-Ex.270 13,18,21,22-tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-yl]benzenesulfonamide N-[(9S,11S,15S)-11-hydroxy-18,21-dimethy1-14,19-dioxo-7-oxa-3-thia-Ex.271 13,18,21,22-tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-yl]methanesulfonami de methyl N-[(9S,11S,15S)-11-hydroxy-18,21-dimethy1-14,19-dioxo-7-oxa-3-Ex.272 thia-13,18,21,22-tetraazatetracyclop 8.2.1.026.09,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-ylicarbamate N-[(9S,11S,15S)-11-hydroxy-18,21-dimethy1-14,19-dioxo-7-oxa-3-thia-Ex.273 13,18,21,22-tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-y1W-methylurea N-[(9S,11S,15S)-11-hydroxy-18,21-dimethy1-14,19-dioxo-7-oxa-3-thia-Ex.274 13,18,21,22-tetraazatetracyclo[18.2.1.026.09,13]tricosa-1(22),2(6) ,4,20 (23)-tetraen-15-y1]-N4-(3-pyridinyOurea N-[(9S,11S,15S)-11-methoxy-18,21-dimethy1-14,19-dioxo-7-oxa-3-thia-Ex.275 13,18,21,22-tetraazatetracyclo[18.2.1.026.09,13]tricosa-1(22),2(6) ,4,20 (23)-tetraen-15-y1]-2-(2-naphthyl)acetamid e N-[(9S,11S,15S)-11-hydroxy-18,21-dimethy1-14,19-dioxo-7-oxa-3-thia-Ex.276 13,18,21,22-tetraazatetracyclo[18.2.1.026.0913]tricosa-1(22),2(6),4,20(23)-tetraen-15-y1W-(2-naphthyl)urea N-[(9S,11S,15S)-11-hydroxy-18,21-dimethy1-14,19-dioxo-7-oxa-3-thia-Ex.277 13,18,21,22-tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-y1]-2-phenylacetamide N-[(9S,11S,15S)-11-hydroxy-18,21-dimethy1-14,19-dioxo-7-oxa-3-thia-Ex.278 13,18,21,22-tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-y1]-3-methoxybenzamide N-[(9S,11S,15S)-11-hydroxy-18,21-dimethy1-14,19-dioxo-7-oxa-3-thia-Ex.279 13,18,21,22-tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-y1]-2-naphthalenesulfonamide 3-(4-fluoropheny1)-N-[(9S,11S,15S)-11-hydroxy-18,21-dimethy1-14,19-Ex.280 dioxo-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-yl]propanamide N-[(9S,11S,15S)-11-hydroxy-18,21-dimethy1-14,19-dioxo-7-oxa-3-thia-Ex.281 13,18,21,22-tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6) ,4,20(23)-tetraen-15-y1]-2-(1H-indo1-3-yl)acetami de (9 S,11S,15S)-11-hyd roxy-18,21-d imethy1-15-1[2-(2-naphthypethyliam ino)-Ex.282 7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraene-14,19-dione (9S,11S,15S)-15-[(4-fluorobenzyl)amino]-11-hydroxy-18,21-dimethy1-7-Ex.283 oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraene-14,19-dione benzyl N-[(13S,19S)-4,8-dimethy1-23-nitro-7,14-dioxo-21-oxa-3,8,15,27-Ex.284a tetraazatetracyclo[20.2.2.12,6.015,19Theptacosa-1(24),2(27),3,5,22,25-hexaen-13-yllcarbamate benzyl N-[(13R,19S)-4,8-dimethy1-23-nitro-7,14-dioxo-21-oxa-3,8,15,27-EX.284b tetraazatetracyclo[20.2.2.12,6.015,19Theptacosa-1(24),2(27),3,5,22,25-hexaen-13-yl]carbamate (13S,19S)-13-amino-4,8-dimethy1-23-nitro-21-oxa-3,8,15,27-Ex.285 tetraazatetracyclo[20.2.2.12,6.015,19]heptacosa-1(24),2(27),3,5,22,25-hexaene-7,14-dione benzyl N-[(13S,19S)-23-amino-4,8-dimethy1-7,14-dioxo-21-oxa-3,8,15,27-Ex.286 tetraazatetracyclo[20.2.2.12,6.015,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-13-ylicarbamate benzyl N-[(13S,19S)-23-(acetylamino)-4,8-dimethy1-7,14-dioxo-21-oxa-Ex.287 3,8,15,27-tetraazatetracyclo[20.2.2.12,6.015,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-13-ylicarbamate N-[(13S,19S)-13-amino-4,8-dimethy1-7,14-dioxo-21-oxa-3,8,15,27-Ex.288 tetraazatetracyclo[20.2.2.125.015,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-23-yllacetamide N-(2-chloropheny0-1V-[(13S,19S)-4,8-dimethyl-23-nitro-7,14-dioxo-21-oxa-Ex.289 3,8,15,27-tetraazatetracyclo[20.2.2.12,6.015,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-13-yl]urea N-[(13S,19S)-23-amino-4,8-dimethy1-7,14-dioxo-21-oxa-3,8,15,27-Ex.290 tetraazatetracyclo[20.2.2.12,6.015,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-13-y1]-/V-(2-chlorophenyOurea N-[(13S,19S)-13-{[(2-chloroanilino)carbonyl]amino}-4,8-dimethyl-7,14-Ex.291 dioxo-21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.12,6.015,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-23-yl]methanesulfonamide N-[(13S,19S)-4,8-dimethy1-23-nitro-7,14-dioxo-21-oxa-3,8,15,27-Ex.292 tetraazatetracyclo[20.2.2.12.6.015,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-13-ylicyclopropanecarboxamide N-[(13S,19S)-23-amino-4,8-dimethy1-7,14-dioxo-21-oxa-3,8,15,27-Ex.293 tetraazatetracyclo[20.2.2.12,6.015,19Theptacosa-1(24),2(27),3,5,22,25-hexaen-13-yl]cyclopropanecarboxamide N-[(13S,19S)-4,8-dimethy1-23-[(methylsulfonyl)amino]-7,14-dioxo-21-oxa-Ex.294 3,8,15,27-tetraazatetracyclo[20.2.2.126.015,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-13-yUcyclopropanecarboxamide N-[(13S,19S)-13-amino-4,8-dimethy1-7,14-dioxo-21-oxa-3,8,15,27-Ex.295 tetraazatetracyclo[20.2.2.12,6.015,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-23-yl]methanesulfonamide benzyl N-[(13S,19S)-4,8-dimethy1-23-[(methylsulfonypamino]-7,14-dioxo-Ex.296 21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.12,6.015,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-13-yllcarbamate benzyl N-[(13S,19S)-4,8-dimethy1-7,14-dioxo-23-(2-pyrimidinylamino)-21-Ex.297 oxa-3,8,15,27-tetraazatetracyclo[20.2.2.126.015,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-13-yl]carbamate (13S,19S)-13-amino-4,8-dimethy1-23-(2-pyrimidinylamino)-21-oxa-Ex.298 3,8,15,27-tetraazatetracyclo[20.2.2.12,6.015,19]heptacosa-1(24),2(27),3,5,22,25-hexaene-7,14-dione N-[(13S,19S)-13-(dimethylamino)-4,8-dimethy1-7,14-dioxo-21-oxa-Ex.299 3,8,15,27-tetraazatetracyclo[20.2.2.12,6.015,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-23-yllacetamide N-[(13S,19S)-23-(acetylamino)-4,8-dimethy1-7,14-dioxo-21-oxa-3,8,15,27-Ex.300 tetraazatetracycl o[20.2.2.12,6.015,19Theptacosa-1(24),2(27),3,5,22,25-hexaen-13-y1]-2-phenylacetamide N-[(13S,19S)-13-{[(3-chlorophenyl)sulfonyl]amino)-4,8-dimethy1-7,14-Ex.301 dioxo-21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.12,6.015,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-23-yllacetamide N-[(13S,19S)-13-{[(isobutylamino)carbonyl]amino)-4,8-dimethy1-7,14-Ex.302 dioxo-21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.12,6.015,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-23-yl]acetamide N-[(13S,19S)-4,8-dimethy1-23-[(methylsulfonypamino]-7,14-dioxo-21-oxa-Ex.303 3,8,15,27-tetraazatetracyclo[20.2.2.12,6.015,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-13-y1]-4-fluorobenzamide N-[(13S,19S)-13-[(3-fluorobenzyl)amino]-4 ,8-dimethy1-7,14-dioxo-21-oxa-Ex.304 3,8,15,27-tetraazatetracyclo[20.2.2.12,6.015,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-23-ylimethanesulfonamide benzyl N-[(15R,16aS)-10-methy1-9,12-dioxo-9,10,11,12,15,16,16a,17-Ex.305 octahydro-14H-dibenzokkipyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]carbamate (15R,16aS)-15-amino-10-methy1-10,11,15,16,16a,17-hexahydro-14H-Ex.306 dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecine-9,12-dione (15R,16aS)-15-(dimethylamino)-10-methy1-10,11,15,16,16a,17-Ex.307 hexahydro-14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecine-9,12-dione N-[(15R,16aS)-10-methy1-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-Ex.308 14 H-d ibenzo[i,k]pyrrolo[2,1-c][1 ,4,7]oxadiazacyclododecin-15-yl]acetamide N-[(15R,16aS)-10-methy1-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-Ex.309 14 H-d ibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-y1]-3-methylbutanamide N-[(15R,16aS)-10-methy1-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-Ex.310 14 H-d ibenzo[i, ilpyrrolo[2,1-41,4,7]oxadiazacyclododecin-15-y1]-2-(2-naphthyl)acetamid e N-[(15R,16aS)-10-methy1-9,12-dioxo-9,10,11,12,15,16,16a,17-octa hydro-Ex.311 14 H-dibenzo[i,Ilpyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-y1]-2-(1-naphthyl)acetamide N-[(15R,16aS)-10-methy1-9,12-dioxo-9,10,11,12,15,16,16a,17-octa hydro-Ex.312 14 H-d ibenzo[i,Ilpyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-y11-2-(dimethylamino)acetamide tert-butyl N-(3-[(15R,16aS)-10-methy1-9,12-dioxo-Ex.313 9,10,11,12,15,16,16a,17-octahydro-14H-dibenzopipyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yliamino-3-oxopropyl)carbamate N-[(15R,16aS)-10-methy1-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-Ex.314 14H-d ibenzo[i, k]pyrrolo[2,1-d[1,4,7]oxadiazacyclododecin-15-y1]-3-aminopropanamide N-[(15R,16aS)-10-methy1-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-Ex.315 14 H-d ibenzok flpyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-y1]-3-fluorobenzamide N-[(15R,16aS)-10-methy1-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-Ex.316 14H-dibenzok Ilpyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]isonicotinamide N-[(15R,16aS)-10-methy1-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-Ex.317 14 H-dibenzo[i,k]pyrrolo[2,1-c][1 ,4,7]oxadiazacyclododecin-15-y1W-methylurea N-[(15R,16aS)-10-methy1-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-Ex.318 14 H-d ibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-y1W-(3-pyridinyl)urea ¨

2-methoxyethyl N-[(15R,16aS)-10-methy1-9,12-dioxo-Ex.319 9,10,11,12,15,16,16a,17-octahydro-14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]carbamate tert-butyl 31({[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-Ex.320 octahydro-14H-dibenzoRk]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yliaminolcarbonyl)amino]propanoate 34({[(15R,16aS)-10-methy1-9,12-dioxo-9,10,11,12,15,16,16a,17-Ex.321 octahydro-14H-dibenzoRk]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]amino}carbonyl)amino]propanoic acid N-[(15R,16aS)-10-methy1-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-Ex.322 14 H-d ibenzo[i, klpyrrolo[2,1-c][1,4,7]oxad iazacyclododecin-15-yl]methanesulfonamide N-[(15R,16aS)-10-methy1-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-Ex.323 14 H-d ibenzo[411 pyrrolo[2,1-c][1 ,4,7]oxadiazacyclododecin-15-yl]benzenesulfonamide (15R,16aS)-15-[(3-fluorobenzypamino]-10-methy1-10,11,15,16,16a,17-Ex.324 hexahydro-14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecine-9,12-dione (15R,16aS)-15-(isobutylamino)-10-methy1-10,11,15,16,16a,17-hexahydro-Ex.325

14 H-d ibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecine-9,12-done N"-[(15R,16aS)-10-methy1-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-Ex.326 14 H-dibenzo[i, k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-y1]-N,N, N',At-tetramethylguanidine benzyl (16S,18S)-16-Rtert-butoxycarbonyl)amino]-7,13-dioxo-4-(trifluoromethyl)-5,20-dioxa-3,8,11,14-Ex.327 tetraazatetracyclo[19.3.1.02,6.014,18]pentacosa-1(25),2(6),3,21,23-pentaene-11-carboxylate tert-butyl N-[(16S,18S)-7,13-dioxo-4-(trifluoromethyl)-5,20-dioxa-Ex.328 3,8,11,14-tetraazatetracyclo[19.3.1.02,6.014,18]pentacosa-1(25),2(6),3,21,23-pentaen-16-yl]carbamate benzyl (16S,18S)-16-amino-7,13-dioxo-4-(trifluoromethyl)-5,20-dioxa-Ex.329 3,8,11,14-tetraazatetracyclo[19.3.1.02,6.014,19pentacosa-1(25),2(6),3,21,23-pentaene-11-carboxylate ally! N-[(12R,16S,18S)-16-[(tert-butoxycarbonyl)amino]-8,13-dioxo-20-Ex.330 oxa-9,14-diazatetracyclo[19.3.1.027.014,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-yl]carbamate ally N-[(12R,16S,18S)-16-amino-8,13-dioxo-20-oxa-9,14-Ex.331 diazatetracyclo[1 9.3.1.02,7.014,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-yllcarbamate 2-(1 H-imidazol-1-y1)-N-[(12R,16S,18S)-12-{[2-(1-naphthypacetyl]a min*
Ex.332 8,13-dioxo-20-oxa-9,14-diazatetracyclo[19.3.1.02,7.014,18]pentacosa-1(25),2,4,6,21,23-hexaen-16-yl]acetamide N-[(12R,16S,18S)-8,13-dioxo-16-{[(3-pyridinylamino)carbonyl]amino}-20-Ex.333 oxa-9,14-diazatetracyclo[19.3.1.02,7.014,181pentacosa-1(25),2,4,6,21,23-hexaen-12-y1]-2-(1-naphthypacetamide 2-(3-chlorophenyI)-N-[(12 R,16S,18S)-8,13-dioxo-16-{[2-(1-pyrrolid inyl)acetylja mino}-20-oxa-9,14-Ex.334 diazatetracyclo[19.3.1.02,7.014,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-yl]acetamide 2-cyclohexyl-N-[(12R,16S,18S)-8,13-dioxo-16-{[2-(1-pyrrolidinyl)acetyl]am ino}-20-oxa-9,14-Ex.335 diazatetracyclop 9.3.1.02,7.014,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-yl]acetamide N-[(12R,16S,18S)-12-{[(1-naphthylamino)carbonyl]amino)-8,13-dioxo-20-Ex.336 oxa-9,14-diazatetracyclo[19.3.1.02,7.014,18]pentacosa-1(25),2,4,6,21,23-hexaen-16-y1]-2-(1-pyrrolidinypacetamide N-[(12R,16S,18S)-12-[(benzylsulfonyl)amino]-8,13-dioxo-20-oxa-9,14-Ex.337 diazatetracyclo[l 9.3.1.02,7.014,18]pentacosa-1(25),2,4,6,21,23-hexaen-16-y1]-2-(1-pyrrolidinypacetamide benzyl N-[(12R,16S,18S)-8,13-dioxo-16-{[2-(1-pyrrolidinypacetyllamino)-Ex.338 20-oxa-9,14-d iazatetracyclo[I 9.3.1.02,7.014,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-ylicarbamate N-[(12R,16S,18S)-12-amino-8,13-dioxo-20-oxa-9,14-Ex.339 diazatetracyclo[19.3.1.02,7.014,18]pentacosa-1(25),2,4,6,21,23-hexaen-y1]-2-(1-pyrrolidinyl)acetamide N-[(12R,16S,18S)-12-{[2-(1-naphthyl)ethyliamino}-8,13-dioxo-20-oxa-Ex.340 9,14-di azatetracyclo[1 9.3.1.02,7.014,18]pentacosa-1(25),2,4,6,21,23-hexaen-16-y1]-2-(1-pyrrolidinyl)acetamide N-[(9S,11R)-1 6-(3-fluorobenzy1)-14,20-dioxo-7-oxa-13,16,19,23-Ex.341 tetraazatetracyclo[19.3.1.12,6.09,13Thexacosa-1(25),2(26),3,5,21,23-hexaen-11-y1]-2-(1-naphthypacetamide N-[(9S,11R)-16-(3-fluorobenzy1)-14,20-dioxo-7-oxa-13,16,19,23-Ex.342 tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-y1]-2-(2-naphthypacetamide N-[(9S,11R)-1 6-(3-fluorobenzy1)-14,20-dioxo-7-oxa-13,16,19,23-Ex.343 tetraazatetracyclo[l 9.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yll-N1-(2-naphthyOurea N-[(9S,11R)-16-(3-fluorobenzy1)-14,20-dioxo-7-oxa-13,16,19,23-Ex.344 tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-y1]-2-naphthalenesulfonamide N-[(9S,11R)-1 6-(3-fluorobenzy1)-14,20-dioxo-7-oxa-13,16,19,23-Ex.345 tetraazatetracyclo[19.3.1 .12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-y1]-3-(2-naphthyl)propanamide N-[(9S,11R)-16-(3-fluorobenzy1)-14,20-dioxo-7-oxa-13,16,19,23-Ex.346 tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-y1]-3-phenylpropanamide 2-(d imethylamino)-N-[(9 S,11R)-16-(3-fluorobenzy1)-14,20-dioxo-7-oxa-Ex.347 13,16,19,23-tetraazatetracyclo[19.3.1.12,6.09,13Thexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]acetamide benzyl (9 S,11R)-11-{[2-(2-naphthyl)acetyl]am ino}-14,20-dioxo-7-oxa-Ex.348 13,16,19,23-tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaene-16-carboxylate N-[(9S,11R)-14,20-dioxo-7-oxa-13,16,19,23-Ex.349 tetraazatetracyclo[19.3.1.126.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-y1]-2-(2-naphthy)acetamide N-[(9S,11R)-16-(3-fluorobenzoy1)-14,20-dioxo-7-oxa-13,16,19,23-Ex.350 tetraazatetracycl o[19.3.1.12,6.09,13Thexacosa-1(25),2(26),3,5,21,23-hexaen-11-y1]-2-(2-naphthyl)acetam id e N-[(9S,11R)-16-benzy1-14,20-dioxo-7-oxa-13,16,19,23-Ex.351 tetraazatetracyclo[19.3.1.12,6.09,13Thexacosa-1(25),2(26),3,5,21,23-hexaen-11-y1]-2-(2-naphthyl)acetamide N-[(9S,11R)-14,20-dioxo-16-phenethy1-7-oxa-13,16,19,23-Ex.352 tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-y11-2-(2-naphthypacetamide N-[(9S,11R)-14,20-dioxo-16-(3-phenylpropy1)-7-oxa-13,16,19,23-Ex.353 tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-y1]-2-(2-naphthypacetamide N-[(9S,11R)-16-isopenty1-14,20-dioxo-7-oxa-13,16,19,23-Ex.354 tetraazatetracyclo[l 9.3.1.12,6.09,11hexacosa-1(25),2(26),3,5,21,23-hexaen-11-y1]-2-(2-naphthypacetamide N-[(9S,11R)-16-isobuty1-14,20-dioxo-7-oxa-13,16,19,23-Ex.355 tetraazatetracyclo[19.3.1.125.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-y1]-2-(2-naphthypacetamide 2-(dimethylamino)ethyl (9S,11R)-11-{[2-(2-naphthyDacetyl]amino}-14,20-Ex.356 dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.12,6.09,13Thexacosa-1(25),2(26),3,5,21,23-hexaene-16-carboxylate N-[(9S,11R)-1 642-(dimethylamino)ethy1]-14,20-dioxo-7-oxa-13,16,19,23-Ex.357 tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-y1]-2-(2-naphthypacetamide 3,3-dimethyl-N-[(9S,11R)-16-methy1-14,20-dioxo-7-oxa-13,16,19,23-Ex.358 tetraazatetracyclo[19.3.1.125.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]butanamide Synthesis of the Building Blocks Readily available examples of amino acids representing subunits of the Bridge C are detailed to the level of fully-defined structures in Table 11. Additional analogs can be accessed smoothly, and a plethora of literature precedents are published.
Therefore this section focuses on synthetic approaches towards building blocks of the Template A and the Modulator B.
Functional groups not involved in ring connections of the macrocyclic backbone can be diversified by standard methods of organic synthesis, preferably by parallel/combinatorial chemistry introducing so-called high variation substituents.
These derivatization methods are well-known to those skilled in the art and do not require further exemplification (selected references: A. R. Katritzky et al.
(eds), Comprehensive Functional Group Transformations, Pergamon, 1995; S. Patai, Z.
Rappoport (eds), Chemistry of Functional Groups, Wiley, 1999; J. March, Advanced Organic Chemistry, 4 ed., Wiley, 1992; D. Obrecht, J.M. Villalgordo (eds), Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries, Pergamon, 1998; W. Bannwarth et al. (eds), Combinatorial Chemistry: From Theory to Application, 2 ed., Wiley-VCH 2006).
a) Synthesis of Template A Building Blocks Over the last decades the coupling to suitably functionalized aromatic or heteroaromatic compounds has reached a highly mature status providing an easy and reliable route to biaryl derivatives of nearly any substitution pattern (cf. leading reviews covering several types of coupling reactions and the references cited therein:
R. M. Kellogg et al., Org. Process Res. Dev. 2010, 14, 30-47; A. de Meijere, F.
Diederich (eds), Metal-Catalyzed Cross-Coupling Reactions, 2nd ed., Wiley-VCH
2004; with focus on heteroaromatic substrates: G. Zeni, R. C. Larock, Chem.
Rev.
2006, 106, 4644-4680; especially for macrocyclic biaryls: Q. Wang, J. Zhu, Chimia 2011, 65, 168-174). Most prominent among these coupling reactions is definitely the Suzuki-Miyaura cross coupling of aryl boronic acid derivatives with aryl halides under palladium catalysis (N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457-2483; S.

Kotha et al., Tetrahedron 2002, 58, 9633-9695; S. L. Buchwald et al., J. Am.
Chem.
Soc. 2005, 127, 4685-4696). Special catalysts, especially the Nolan's catalysts make the Suzuki-Miyaura reaction also amenable to highly sterically hindered substrates (S. P. Nolan et al., J. Am. Chem. Soc. 2003, 125, 16194-16195; S. P. Nolan et al., Org. Lett. 2005, 7, 1829-1832). More recent developments broadened the scope of the Suzuki coupling from aryl halides to other substrates like aryl mesylates (F.Y.
Kwong et al., Angew. Chem. mt. Ed. 2008, 47, 8059-8063) or aryl carbamates, carbonates and sulfamates (N. K. Garg et al., J. Am. Chem. Soc. 2009, 131, 17749).
The biaryl compounds obtained by such coupling protocols might require further functional group transformations as described below.

General Functional Group Interconversions The majority of the Templates A are carrying an aromatic or heteroaromatic hydroxy (¨OH) or sulfanyl (thiol) group (¨SH) in the AB substructure and a carboxylic acid group (¨COOH) or sulfanyl moiety (¨SH) or its respective oxidation products in the Ac substructure.
As more phenolic precursors are commercially available than the corresponding thiophenols, a transformation of a phenol into a thiophenol might be required.

Alternatively thiophenols might be derived from the corresponding aryl halides or diazonium salts. Selected functional group transformations for introducing a sulfanyl group (¨SH), i.e. Ar/Hetar¨X Ar/Hetar¨SH (X= OH, F, Cl, Br, I, N2+), are the compiled below (T-I to T-VII):
T-I: A sequence of broad applicability is the transformation of a phenol into a thiocarbamate with N,N-dimethylthiocarbamoyl chloride, followed by Newman-Kwart rearrangement and subsequent hydrolysis (A. Gallardo-Godoy et al., J. Med.
Chem.
2005, 48, 2407-2419; P. Beaulieu et al., Bioorg. Med. Chem. Lett. 2006, 16, 4993; H. Sugiyama et al., Chem. Pharm. Bull. 2007, 55, 613-624; S. Lin et al., Org.
Prep. Proced. Int. 2000; 547-556).
T-II: The direct transformation of an ¨OH adjacent to a pyridinic nitrogen (i.e.
equivalent to the pyridone tautomer) can be accomplished by heating with P2S5 (K.
Hirai et al., Heterocycles 1994, 38, 277-280).
T-III: As an alternative to phenols, halogen-substituted (esp. with F or Cl) aromatic ring systems might serve as precursors. In case the halogen is in a position activated by an electron withdrawing group in ortho- or para-position the -SH moiety or a protected surrogate can be introduced under mild conditions by nucleophilic aromatic substitution reactions (SNAr) (G.J. Atwell et al., J. Med. Chem. 1994, 37, 371-380).
Especially in the field of heterocyclic compounds, where the electron withdrawing effect is exerted by pyridine-like nitrogen atoms, this type of substitution is often utilized (S. McCombie et al., Heterocycles, 1993, 35, 93-97).
T-IV: Similarly, in Sandmeyer-type reactions a diazonium group (¨N2+) can be replaced (C. Mukherjee, E. Biehl, Heterocycles 2004, 63, 2309-2318).
T-V: In positions not activated for an SNAr the substitution of halogen atoms (esp. Br or I) can be accomplished via the corresponding organolithium or Grignard reagents (J.L. Kice, A. G. Kutateladze, J. Org. Chem. 1993, 58, 917-923; P.C. Kearney et al., J. Am. Chem. Soc. 1993, 115, 9907-9919). Alternatively, transition metal-catalyzed transformations are feasible for this type of reaction, e.g. Cu-catalyzed substitution with benzothioic S-acid (N. Sawada et al., Tetrahedron Lett. 2006, 47, 6595-6597), or Pd-catalyzed substitution with KS-Si(i-Pr)3 followed by desilylation of the introduced ¨
SSi(i-Pr)3 group (A. M. Rane et al., Tetrahedron Lett. 1994, 35, 3225-3226).
The thus introduced ¨SH moieties constitute a thia-bridge ¨S¨ in the later 5 macrocyclic products and can be selectively transformed into higher oxidation states.
Therefore the building blocks with sulfanyl moieties are also regarded as building blocks for the introduction of sulfinyl (¨S(=0)¨; i.e. sulfoxide) and sulfonyl (¨S(=0)2¨;
i.e. sulfone) moieties. Suitable oxidation methods are:
T-VI: The selective oxidation of a thioether (¨S¨) to a sulfoxide (¨S(=0)¨) can be 10 highly selectively and mildly achieved with hexamethylenetetramine-bromine HMTAB
(K. Choudhary et al.; J. Phys. Org. Chem. 2000, 13, 283-292); under these conditions primary hydroxyl groups for example are not affected. In a number of related reactions chlorotrimethylsilane showed high selectivity, too (Y.-J. Chen et al., Tetrahedron Lett. 2000, 41, 5233-5236).

15 T-VII: Stronger oxidants directly transfer the sulfanyl (¨S¨) into the sulfonyl group (¨S(=0)2¨). Among the many reagents mentioned in literature the system periodic acid/ chromium(VI)oxide for example can be applied in the presence of C=C-double bonds (US2007/293548 Al).
20 Hydroxyl groups attached to aromatic rings (Ar¨OH or Heteroaryl¨OH) in turn, if not already part of a synthesized or commercially available biaryl, can be introduced by various methods, e.g. H-I to H-IV:
H-I: Analogously to T-III) the hydroxy group or its surrogate can be introduced by an SNAr reaction of halogen atoms, esp. Cl or F, ortho or para to an electron withdrawing 25 substituent (W. Cantrell, Tetrahedron Lett, 2006, 47, 4249-4251) or to a pyridinic nitrogen atom (S.D. Taylor et al., J. Org. Chem. 2006, 71, 9420-9430).
H-II: Sandmeyer-type hydroxylations of aromatic amines via intermediate diazonium salts (P. Madsen et al., J. Med. Chem. 2002, 45, 5755-5775).
H-III: The substitution of halogen atoms (esp. Br and l), which are not activated for an 30 SNAr, can be achieved by transition metal-catalyzed C-0-couplings.
Predominant are Pd-catalysts (K.W. Anderson et al., J. Am. Chem. Soc. 2006, 128, 10694-10695;
B.J.
Gallon et al., Angew. Chem,, Int. Ed. 2007, 46, 7251-7254), but also others find application, like Cu-catalysts (J.E. Ellis, S.R. Lenger, Synth. Commun. 1998, 28, 1517-1524).

H-IV: Of broad scope is also a two-step process which first transforms halogen atoms (CI, Br and I) into a boronate and then oxidatively cleaves the carbon-boron bond to the phenol (J.R. Vyvyan et al., J. Org. Chem. 2004, 69, 2461-2468).
The carboxylic acid group of the biaryl A building blocks, if not already present in commercially available coupling precursors, can be introduced by standard procedures like C-I to C-IV:
C-I: The oxidation of functional groups like hydroxymethyl (¨CH2-0H) or aldehyde (¨C(=0)H) can be achieved under mild conditions (G.V.M. Sharma et al., Synth.
Commun. 2000, 30, 397-406; C. Wiles et al., Tetrahedron Lett. 2006, 47, 5261-5264).
Also methyl groups on benzene rings can be oxidized; however, as harsh reaction conditions are usually required, its applicability is limited. In contrast, the relatively acidic methyl groups ortho or para to a pyridine nitrogen can be oxidized under milder conditions; making this the method of choice for many pyridine analogs (T. R.
Kelly, F. Lang, J. Org. Chem. 1996, 61, 4623-4633).
C-II: Halogen atoms can easily be replaced by a carboxyl group or surrogate thereof, e.g. by halogen metal exchange and subsequent carboxylation of the intermediate Grignard or organolithium species (C.G. Screttas, B.R. Steele, J. Org. Chem.
1989, 54, 1013-1017), or by utilizing Mander's reagent (methyl cyanoformate)(A.
Lepretre et al., Tetrahedron 2000, 56, 265-274).
C-III: In the case that acidified ring positions are to be carboxylated, a viable method is deprotonation with a strong base (usually tert-butyl lithium) followed by carboxylation of the intermediate organolithium species in analogy to C-II).
C-IV: Hydrolysis of ester, amide or nitrile groups. The CN group in turn can easily be introduced by treating organic halides with CuCN (Rosenmund-von Braun reaction:
C. F. Koelsch, A. G. Whitney, J. Org. Chem., 1941, 6, 795-803).
Applied to commercially available starting materials or biarlys obtained by coupling route, these general transformations offer a tool box for accessing a huge variety of Templates A. Additional literature examples are cited below within the sections on specific derivatives.
b) Synthesis of Modulator B Building Blocks The Modulator B moieties of macrocycle I are derived from appropriately substituted aminoalcohols, wherein the amino and alcohol group, which contribute to the ring connectivity, are separated by 2-4 C-atoms.

_ If not already present in a commercial building block, the substituent R6 can be introduced by standard nucleophilic addition of organometallic reagents to carbonyl or carboxyl derivatives. Alkyl (as R6) substituted analogs of B1 and derivatives of B2-B10 with no additional C-substituent on their ring system are commercially available, as are many derivatives with an amino (¨NH2) or alcohol (¨OH) substituent as R6. In the such cases the diversification of the substitution pattern can be easily achieved by standard transformations of the free amine or hydroxy functionalities.
Possible pathways to more complex pyrrolidine derivatives of type B4-B6 or piperidine derivatives of type B7-B9 rely on the same strategy: Intramolecular cyclization reactions are the predominant route applicable to diversely substituted substrates. Amines carrying a residue with a leaving group in the w¨position lead directly to the desired saturated ring systems by intramolecular nucleophilic substitution (G. Ceulemans et al., Tetrahedron 1997, 53, 14957-14974; S. H.
Kang, D. H. Ryu, Tetrahedron Lett. 1997, 38, 607-610; J. L. Ruano et al., Synthesis 2006, 687-691). Also N-haloamines can be directly transformed into the desired compounds by a Hofmann¨Loffler¨Freytag reaction (M. E. Wolff, Chem. Rev. 1963, 63, 55-64).
Alternatively, amines carrying two substituents, each with an alkene or alkyne bond, can be subjected to a ring closing metathesis (RCM) reaction (Y. Coquerel, J.
Rodriguez, Eur. J. Org. Chem. 2008, 1125-1132) and subsequent reduction of the partially unsaturated ring to the saturated heterocycle.
Another possible access, reduction of aromatic five- or six-membered heterocycles to their saturated analogs, is described in the literature. Due to the large number of commercially available pyridines this approach is especially useful for the synthesis of the piperidine system (J. Bolos et al., J. Heterocycl. Chem. 1994, 3/, 1493-1496;
A. Solladie-Cavallo et al., Tetrahedron Left. 2003, 44, 8501-8504; R. Naef et al., J.
Agric. Food Chem. 2005, 53, 9161-9164).
General processes for the synthesis of macrocyclic compounds I
General procedures for the synthesis of libraries of macrocyclic compounds of general structure I are described below. It will be immediately apparent to those skilled in the art how these procedures have to be modified for the synthesis of individual macrocyclic compounds of type I.
The macrocyclic compounds of this invention are obtained by cyclization of suitable linear precursors which are derived from optionally substituted bifunctional hydroxy-or mercapto biaryls/heteroaryls X¨AB¨Ac¨Y (Template AB¨Ac), substituted amino alcohols B (Modulator), and one to three building blocks forming Bridge C.
Hydroxy- or mercapto biaryls/heteroaryls X¨AB¨Ac¨Y consist of two optionally substituted building blocks X¨AB and Ac¨Y. Building blocks X¨AB comprise hydroxyaryl, hydroxyheteroaryl-, mercaptoaryl- and mercaptoheteroaryl compounds.
Building blocks Ac¨Y comprise carboxyaryl-, carboxyheteroaryl-, mercaptoaryl-, mercaptoheteroaryl, alkenylaryl, and alkenylheteroaryl compounds. X¨AB and Ac¨Y
are six-membered aromatic or five- or six-membered heteroaromatic rings.
Templates X¨AB-Ac¨Y can be obtained by combination of two six-membered rings, two five-membered rings or a five- and a six-membered ring. The building blocks X¨AB and Ac¨Y are connected by a carbon-carbon bond to form the biaryls X¨AB¨Ac¨Y.
Variable substituents are introduced by pre¨ or postcyclative derivatization of one or more orthogonally protected functional group (e.g. amino groups, carboxyl groups, hydroxyl groups) attached to B, C or A. Variable R-groups may also be introduced as side chain motifs of the subunits of Bridge C.
The macrocyclic products of this invention can be prepared either in solution or on solid support.
The essential ring closure reaction is possible between any of the building blocks;
and macrocycles I are obtained by e.g.
= Macrolactamization between C and B;
= Macrolactamization between AB-Ac and C;
= Macrolactamization between any two subunits of Bridge C;
= Arylether or arylthioether formation between AB-Ac and B;
= Arylthioether formation between AB-Ac and C;
= Biaryl synthesis by coupling reaction (e.g. Suzuki coupling) between AB
and Ac;
= Ring closing metathesis (RCM) reaction between any two subunits of C or upon formation of such a subunit;
= Ring closing metathesis reaction between AB-Ac and C.
SW-1: Synthesis workflow for the preparation of side-chain protected macrocycles I
by macrolactamization in solution Macrocycles of structure I with orthogonally protected exocyclic functional groups (attachment points for derivatizations) are prepared in solution by the process outlined below. Throughout all steps the orthogonal protection of the side chains stays intact and is not affected by protecting group manipulations of the main chain.
al) Condensation of an appropriately protected hydroxy- or mercapto-biaryl/heteroaryl carboxylic acid PG1¨X¨AB¨Ac¨CO2H and a suitable C-terminally and side-chain protected C-subunit building block H¨NR7--cl¨CO¨OPG2 to form PG1--X¨AB¨Ac-CON ¨CO¨OPG2;
bl) If required, deprotection of the aryl/heteroaryl hydroxy or mercapto group;
cl) Aryl/heteroaryl ether or thioether formation with a suitably N-protected amino alcohol PG3¨B¨OH leading to the fully protected linear precursor PG3¨B¨X¨AB¨Ac¨CON ¨C 0-0 PG2;
dl) Cleavage of the "main chain" protective groups affording the free amino acid H¨B¨X¨AB¨Ac¨CONR7¨cl¨CO¨OH, which is subjected to macrocyclization el) Intramolecular amide coupling to cyc/o(B¨X¨AB¨Ac¨CONR7¨cl¨00¨) as macrocyclic product.
In addition to the steps described above, chain elongation by one or two additional C-subunits (c2, c3) and subsequent macrolactamization starts with coupling of a second suitably C-protected amino acid to the free carboxylic acid functionality of the product obtained by N-reprotection of the product of step di. Cleavage of the main chain protective groups and either macrolactamization or repetition of the chain elongation steps and macrolactamization provides either cyc/o(B¨X¨A6¨Ac¨CONR7--cl¨
CO N IV¨c2¨00¨) or cyc/o(B¨X¨AB¨Ac¨CON R7¨cl ¨CON R7-c2-CON1:27¨c3¨00-) .
The free carboxylic acid functionality of the N-reprotected product derived from any of the three linear macrolactamization precursors (product of step dl, or corresponding product after coupling of one or two additional C-subunits) can be further elaborated by chain extensions/ homologizations (e.g. Arndt-Eistert reaction) or functional group interconversions like Curtius rearrangement ultimately affording homologous macrocycles or those where the connection between Modulator B and Bridge C
corresponds to a urea moiety.
SW-2: Synthesis workflow for the preparation of side-chain protected macrocycles I
by macrolactamization in solution As an alternative to SW-1 the intermediate H¨X¨AB¨Ac¨Y¨Z¨c1¨CO¨OPG2(product of step bl) can be prepared by a2) S-alkylation of a suitable mercapto-substituted haloaryl/heteroaryl compound Hal-Ac-SH (Hal represents a halogen atom) with a C-terminally and side-chain protected C-subunit building block LG¨CHR8¨c1¨CO¨OPG2(LG represents a leaving group like halide, alkyl-, arylsulfonate or activated OH like e.g. under Mitsunobu conditions);
b2) Suzuki coupling reaction between the product of step a2) and a suitable hydroxyl-substituted boronic acid or boronic ester HX-AB-B(OR)2 leading Co HX-AB-Ac-S-5 c1-CO-OPG2.
In analogy, amide coupling of a suitable C-terminally and side-chain protected C-subunit building block H¨NR7--c1¨CO¨OPG2to a haloaryl/heteroaryl carboxylic acid Hal-Ac-CO-OH and subsequent Suzuki biaryl coupling reaction with a suitable hydroxyl-substituted boronic acid or boronic ester would provide H¨X-AB-10 Ac¨CONR7¨cl ¨CO¨OPG2.
Possible subsequent steps are as described in SW-1, providing cyc/o(B¨X¨AB-Ac¨Y-Z¨c1¨00¨) with Y-Z = CONR7, S-CHR8.
Oxidation of cyc/o(B¨X¨AB-Ac¨S-CHR8¨c1¨00¨) leads to the corresponding sulfoxides cyclo(B¨X¨AB-Ac¨SO-CHR8¨cl¨00¨) or sulfone cyc/o(B¨X¨AB-Ac--502-15 CHR8¨c1¨00--).
SW-3: Synthesis workflow for the preparation of side-chain protected macrocycles I
by macrolactamization in solution As an alternative to SW-1 the protected cyclization precursor PG3¨B¨X-AB-Ac-20 CONR7¨c1¨CO¨OPG2 can also be synthesized by an inverted order of reaction steps:
a3) Arylether or arylthioether formation between a hydroxyl or mercapto-aryl/heteroaryl ester H-X-AB-Ac¨CO¨OPG4 and a suitably protected amino alcohol PG3¨B¨OH to afford PG3¨B¨X-AB-Ac¨CO¨OPG4.
25 Further more, PG3¨B¨X-AB-Ac¨CO¨OPG4 can also be obtained by arylether or arylthio ether formation between a suitably protected aminoalcohol PG3¨B¨OH
and an optionally substituted hydroxyl- or mercaptoaryl halide or heteroaryl halide HX¨AB-Hal leading to PG3¨B¨X¨A6-Hal and subsequent coupling of an optionally substituted alkoxycarbonyl aryl or heteroaryl boronic acid or boronic ester (R0)2B-Ac-CO-OPG4.
30 b3) Deprotection of the carboxylic acid group to PG3¨B¨X¨AB-Ac¨CO-OH;
c3) Condensation with a C-terminally and side-chain protected building block H¨NR7¨c1¨CO¨OPG2 to PG3¨B¨X-A8-Ac¨CONR7--c1¨CO¨OPG2.
Possible subsequent steps are as described in SW-1.
35 In analogy to step c3), PG3¨B¨X¨A6-Ac¨CO2H can be coupled to a previously formed di- or tripeptide leading to protected cyclization precursors such as PG3-B¨X¨Aa-Ac¨CON R7¨cl ¨CON R7-c2 -00-0 PG2 or PG3-B¨X¨AB-Ac¨CON R7¨c1¨C ON R7-c2-CONR7-c3-CO¨OPG2. If applying this approach for the synthesis of macrocycles I, the synthesis is best performed by preparation of the linear N-terminal deprotected cyclization precursor on solid support, followed by release from resin and cyclization as well as cleavage of side chain protective groups in solution, as detailed in SW4.
SW-4: Synthesis workflow for the preparation of side-chain protected macrocycles I
by combined solid phase and solution phase chemistry Macrocyclic compounds of general formula I with highly variable side chain motifs in Bridge C can advantageously be prepared in parallel array synthesis applying a combination of solid phase and solution phase synthesis methodologies.
The solid support (polymer, resin) is preferably a trityl resin e.g.
chlorotrityl chloride resin (cross-linked with 1-5% divinylbenzene), which is useful as polymer-bound protective group for carboxylic acids (D. Obrecht, J.-M. Villalgordo, Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries, Tetrahedron Organic Chemistry Series, Vol. 17, Pergamon 1998; K. Barbs et al., mt.
J. Peptide Protein Res. 1991, 37, 513-520; K. Barbs et al., Angew. Chem. Int.
Ed.
1991, 30, 590-593).
a4) The suitably side-chain protected C-subunit PG5NR7-c2-CO-OH is attached to the solid support;
b4) The N-terminal protective group is cleaved;
c4) The suitably side-chain protected C-subunit PG5NR7-c1-CO-OH is coupled;
subsequent N-terminal deprotection leads to HNR7-c1-CO-NR7-c2-00-0-chlorotrityl resin;
d4) Coupling of a suitably side chain protected building block PG3¨B¨X¨AB-Ac¨00-OH (cf. SW-3, product of step b3) and cleavage of the N-terminal protective group;
e4) Release of the linear main-chain deprotected macrolactamization precursor H-B¨X¨AB-Ac¨CONR7¨cl¨CONR7-c2-CO¨OH from the resin;
f4) Macrolactamization to cyc/o(B¨X¨AB-Ac¨CONR7¨c1¨CONR7-c2-00-).
g4) Optional: Cleavage of protective groups of side-chain functions.
Immobilization of an amino acid PG5NR7-c3-CO-OH and two additional amino acid coupling/deprotection cycles would lead to HNIR7-c1-CO-NR7-c2-CO-NR7-c3-00-0-chlorotrityl resin. Possible subsequent steps are as described above, providing cyclo(B¨X¨AB-Ac¨C N IR7¨c1 ¨CON R7-c2-CO-N R7-c3-CO-).

The ring closure of linear precusors like H-B¨X¨AB-Ac¨CONR7¨c1¨CONR7-c2-CO¨OH may be achieved using soluble coupling reagents as described below or by engaging polymer-supported coupling reagents such as N-cyclohexyl-carbodiimide-/V-methylpolystyrene or N-alkyl-2-chloro pyridinium triflate resin (S.
Crosignani et al, Org. Lett. 2004, 6, 4579-4582).
Further viable alternatives for the synthesis of macrocycles I by combined application of solid phase and solution phase conditions could involve macrolactamization in other positions, e.g. between two subunits in Bridge C. Alternative cyclization precursors like H-NR7-c2-CO-B-X-AB-Ac-CONR7-c1 -CO-OH can be obtained from the same building blocks (as described for SW4) by changing the sequence of coupling/deprotection steps.
SW-5: Synthesis workflow for the preparation of side-chain protected macrocycles I
by ring-closing metathesis in solution Ring-closing metathesis (RCM) of olefinic precursors was applied for the synthesis of subunits of Bridge C, wherein e.g. c2 = c2'-c2":
a5) Coupling of an optionally substituted alkenyl amine building block H¨NR7¨c1-V-c2'=CH2 with suitably protected carboxylic acid derivatives PG1¨X-AB-Ac-CO2H
to afford PG1¨X-AB-Ac-CO-NR7¨c1-V-c2'=CH2;
b5) if required release of the aryl/heteroaryl hydroxyl or mercapto group;
c5) Arylether or arylthioether formation between H¨X-AB-Ac-CO-NR7¨c1-V-c2'=CH2 and PG3¨B¨OH leading to PG3¨B¨X-AB-Ac-CO-NR7¨c1-V-c2'=CH2 d5) Cleavage of the N-terminal protective group leading to H¨B¨X-AB-Ac-00-N R7¨c1-V-c2'=CH 2 e5) Coupling of a suitable (optionally substituted and suitably protected) enoic acid to H2C=c2"-CO¨B¨X-AB-Ac-CO-NR7¨c1-V-c2'=CH2;
f5) Ring-closing metathesis to cyclo(c2"-CO¨B¨X-AB-Ac-CO-NR7¨c1-V-c2') [= cyc/o(B¨X-AB-Ac-CO-N R7¨c1 -V-c2-00¨)]
g5) Optional: Hydrogenation of the newly formed C-C double bond of the metathesis product.
In addition, it is also feasible to prepare olefinic macrocycles with modified Bridges C
such as cyc/o(B¨X-AB-Ac-Y-Z¨c1¨V¨c2¨CO-NR7¨c3¨00¨), or cyclo(B¨X-AB-Ac-Y-Z¨c1¨00¨), and subsequently the respective hydrogenated analogs.

General procedures for synthetic steps utilized in SW-1 to SW-5 In all general procedures below Y-Z represents CONRn or SCHRn.
Amidation reactions (steps at c3, a5, e5) An appropriately protected (preferably as acetyloxy or acetylmercapto) and optionally substituted biaryl/heteroaryl carboxylic acid (PG3¨X-A3-Ac¨CO2H) or a more advanced intermediate like PG3¨B-X-AB-Ac¨CO2H is condensed with a suitably protected amino acid ester H¨NR7¨c1¨CO¨OPG2 or an amine H¨NR7--c1-V-c2'=CH2 in the presence of a coupling reagent (e.g. benzotriazole derivatives like HBTU, HCTU, BOP, PyBOP; their aza analogs like HATU; or carbodiimides like EDC;
others like PyClu, T3P), an auxiliary base (e.g. i-Pr2NEt, Et3N, pyridine, collidine) in solvents like CH2Cl2, DMF, pyridine. Benzotriazole-based coupling reagents and carbodiimides can be used together with suitable auxiliary reagents HOBt or HOAt.
Hydroxybiaryl/heteroaryl carboxylic acids H-X-AB-Ac¨CO2H do not necessarily require protection of the phenolic OH-group and can directly be coupled with the H¨N ¨CO¨OPG2 to the free phenol derivative H¨X¨AB-Ac-CON R7¨c1¨CO¨OPG2-As an alternative, the amidation can also be accomplished with the corresponding acid derivatives like acid chlorides, anhydrides, or active esters.
Deprotection of aromatic hydroxy or mercapto groups (steps b1, b5) Deacylation of PG1¨X-AB-Ac¨CONR7¨c1¨CO¨OPG2 or PG1¨X-AB-Ac-CO-NR7¨c1-V-c2'=CH2 to the corresponding free hydroxyl or mercapto aryl/heteroaryl amide H¨X-As-Ac¨CONR7¨cl¨CO¨OPG2 or H¨X-AB-Ac-CO-NR7--c1-V-c2'=CH2 is achieved by aminolysis, which is advantageously carried out with a dialkylaminoalkyl amine in solvents like degassed THF at 0-25 C. Acyl amine side products formed in the course of the reaction are easily removed by extraction with acidic aqueous solutions.
Arylether or arylthioether formation between A and B (steps c1, a3, c5) Alkylation of the phenol or thiophenol like H¨X-AB-Ac¨Y-Z¨c1¨CO¨OPG2, H-X-AB-A0¨CO¨OPG4, or H¨X-AB-Ac-CO-NR7¨c1-V-c2'=CH2 with a suitably N-protected amino alcohol PG3¨B¨OH to the ether or thioether PG3¨B-X-A3-Ac¨Y-Z¨c1¨CO¨OPG2, PG3¨B-X-AB-Ac¨CO¨OPG4, or PG3¨B-X-A5-Ac-CO-NR7¨c1-V-c2'=CH2 is accomplished with azodicarboxylic acid derivatives such as DEAD, DIAD, TMAD or ADDP in the presence of trialkyl or triaryl phosphines in solvents like benzene, toluene, CH2Cl2, CHCI3 or THF at 0 C to room temperature. As a variation, the reaction is performed with CMBP in toluene at temperatures of 20-110 C.

In an alternative approach, the alcohol PG3¨B¨OH is converted into the corresponding sulfonate (e.g. mesylate, tosylate or triflate) or halide (e.g.
chloride, bromide or iodide) and subsequently treated with the phenol/thiophenol H-X-AB-Ac¨CO¨OPG4 in the presence of an auxiliary base such as NaH or K2CO3 in solvents like DMF, DMSO, NMP, HMPA, or THF, to yield PG3¨B-X-AB-Ac¨CO¨OPG4.
Cleavage of the main chain protective groups (step dl) Simultaneous or stepwise cleavage of the main chain protective groups provides the linear amino acids as cyclization precursors. The preferred protecting groups are Alloc as PG3 and/or allylester as PG2, which can be cleaved simultaneously by palladium catalysts (e.g. Pd(PPh3)4) in the presence of 1,3-dimethyl barbituric acid in solvents like CH2Cl2 or Et0Ac or mixtures thereof.
Also applied were Boc as PG3 and methyl, ethyl or tert-butyl ester as PG2. Boc and groups and t-Bu esters are cleaved either with TFA in CH2Cl2 or with HCI-dioxane.
Methyl or ethyl esters are best saponified with aq. LiOH in mixtures of Me0H
and THF.
Macrolactamization (steps el, f4) Macrolactamization occurs upon treatment of the cyclization precursor with coupling reagents like T3P or FDPP (if required in the presence of an auxiliary base such as i-Pr2NEt) in solvents like CH2Cl2 or DMF under high dilution conditions and at temperatures ranging from 20 to 100 C.
Due to their synthetic importance, macrolactamizations are a well-investigated class of transformations. The favorable application of FDPP as cyclization mediator is described e.g. by J. Dudash et al., Synth. Commun. 1993, 23, 349-356; and R.
Samy et al., J. Org. Chem. 1999, 64, 2711-2728. Many other coupling reagents were successfully utilized in related head to tail cyclizations and might be applied instead;
examples include benzotriazole derivatives like HBTU, HCTU, PyBOP; or their aza analogs such as HATU, as well as DPPA, and carbodiimides like EDC or DIC (P.
Li, P.P. Roller, Curr. Top. Med. Chem. 2002, 2, 325-341; D.L. Boger et al., J. Am.
Chem.
Soc. 1999, 121, 10004-10011). Still another route to macrolactams relies on the intramolecular reaction of an active ester with an in situ released amino group (e.g.
by carbamate deprotection or azide reduction) as demonstrated in the synthesis of peptide alkaloids and vancomycin model systems (U. Schmidt et al., J. Org.
Chem.
1982, 47, 3261-3264; K.C. Nicolaou et al., Chem. Commun. 1997, 1899-1900).

Ring-closing metathesis (RCM) (step f5) Ring-closing metathesis (RCM) of olefinic precursors to macrocyclic compounds is well documented (e.g. A. Furstner et at., Chem. Eur. J. 2001, 7, 4811-4820) and supplements the macrocyclization strategies described above.
The ring-closing metathesis is conveniently performed in solvents like CH2Cl2 or toluene at temperatures of 20-100 C in the presence of indenylidene-ruthenium complexes such as [1,3-bis(2,4,6-trimethylphenyI)-2-imidazolidinylidene]dichloro-[(2-isopropoxy)(5-pentafluorobenzoylamino)benzylidene]ruthenium(I I); dichloro-(3-phenyl -1 H-inden-1-ylidene)bis(tricyclohexyl-phosphine)-ruthenium(I I); [1,3-bis(2,4,6-trimethylpheny1)-2-imidazolidinylidene]-dichloro-(3-phenyl-1H-inden-1-ylidene(tri-cyclohexylphosphine)-ruthenium(1 I); or [1,3-bis(2,4,6-tri-methylpheny1)-2-imidazoli-dinylidene]-dichloro-(3-phenyl-1H-inden-1-ylidene)(pyridyl)ruthenium(II) (S.
Monsaert et al., Eur. J. Inorg. Chem. 2008, 432-440 and references cited therein).
In addition to ring closing transformations described above, biaryl coupling reactions such as intramolecular Suzuki coupling and Suzuki-Miyaura conditions have been applied to prepare macrocyclic compounds with biaryl motifs (M. Kaiser et at., Org.
Lett. 2003, 5, 3435 ¨ 3437; R. Lepine et at., Org. Lett. 2005, 7 , 2981-2984).
The coupling of arylboronato-carboxylic acids to amines is also described (cf ref.
above, M. Kaiser et at., R. Lepine et al.); therefore the synthesis of linear precursors Hal-AB-X-B-CO-c1-NR7-CO-Ac-B(OR)2 (Hal represents a halogen atom or a triflate, B(OR)2 a boronic acid or boronic ester functionality) an their cyclization in a Pd-catalyzed coupling reaction is a feasible alternative.
General procedures for synthetic steps in SW-4 Synthesis of linear cyclization precursors on solid support (steps a4 to e4) Chlorotrityl resins are frequently used in solid phase peptide synthesis.
Therefore, attachment of Fmoc- or Alloc-protected amino acids to these resins as well as subsequent deprotection steps and coupling/deprotection of additional amino acids are well described (K. Barbs et al., mt. J. Peptide Protein Res. 1991, 37, 513-520; K.
Barbs et at., Angew. Chem. mt. Ed. 1991, 30, 590-593). For the examples of the present invention, chlorotrityl chloride resin (matrix: copoly(styrene-1%DVB) is treated with an N-terminally Fmoc-protected amino acid in CH2Cl2 in the presence of an auxiliary base like i-Pr2NEt. Fmoc deprotection (DBU, DMF) and coupling/deprotection of Fmoc- or Alloc-protected amino acids provides a linear, N-terminally deprotected cyclization precursor, still attached to the resin.
Fmoc- or Alloc-protected amino acids are coupled in the presence of reagents like HATU
or PyBOP in DMF in the presence of i-Pr2NEt. Alloc protective groups were removed by treatment of the carbamate with Pd(PPh3)4 and phenylsilane in CH2Cl2. The linear cyclization precursor is then released by treatment of the resin with HFIP in CH2Cl2 (R. Bollhagen et al. J. Chem. Soc. Chem. Commun. 1994, 2559-2560). It is well known, that peptides can also be cleaved from the resin using TFA in CH2Cl2 or mixtures of acetic acid, 2,2,2-trifluoroethanol and CH2Cl2 (K. Barbs et al., Int. J.
Peptide Protein Res. 1991, 37, 513-520). The subsequent macrolactaminzation step is described above.
SW-6: Synthesis workflow for derivatizations of attachment points in solution The macrocyclic compounds obtained according to SW-1 to SW-3 and SW-5 can be further modified by transformations involving functional groups like, but not limited to, amino, carboxyl or hydroxyl groups. In addition, aromatic halides or sulfonates can be subjected to transition-metal catalyzed C-C or C-heteroatom-coupling reactions. The orthogonal protection of the attachment points allows stepwise deprotections and derivatizations which are carried out in a parallel fashion to generate substance libraries:
a6) Cleavage of the first protective group;
b6) Derivatization of the unmasked functional group;
c6) Cleavage of the second protective group;
d6) Derivatization of the liberated functional group; etc.
General procedures for synthetic steps utilized in SW-6 Protecting group cleavage (steps a6 and c6) The utilized amine protecting groups (e.g. Boc, Cbz, Teoc, Alloc, Fmoc, etc.), carboxylic acid protecting groups (e.g. tert-butyl, benzyl, allyl, methyl, etc.) or alcohol protecting groups (e.g. tert-butyl, benzyl, allyl, acetyl, benzoyl, pivaloyl) are removed under standard conditions (P.G.M. Wuts, T.W. Greene, Greene's Protective Groups in Organic Synthesis, John Wiley and Sons, 4th Edition, 2006; P.J. Koncienski, Protecting Groups, 3rd ed., Georg Thieme Verlag 2005).
Aryl nitro groups are reduced to anilines.
Attachment point derivatizations (steps b6 and d6) Derivatizations of the liberated functional groups are based on standard synthesis procedures (A. R. Katritzky et al. (eds), Comprehensive Functional Group _ Transformations, Pergamon, 1995; S. Patai, Z. Rappoport (eds), Chemistry of Functional Groups, Wiley, 1999; J. March, Advanced Organic Chemistry, 4 ed., Wiley, 1992; leading reviews for Mitsunobu reaction: 0. Mitsunobu, Synthesis 1981, 1-28; D.L. Hughes, Org. Reactions; Wiley, 1992, Vol. 42; leading reviews for reductive amination/alkylation: A.F. Abdel-Magid et al., J. Org. Chem. 1996, 61, 3849;
E.W. Baxter, A.B. Reitz, Org. Reactions, Wiley, 2002, Vol. 59).
Such prototypical transformations include, but are not limited to:
(i) Amino group derivatizations such as = Amidations with carbonyl chlorides, carboxylic acid anhydrides, active esters;
or with carboxylic acids in the presence of coupling reagents (cf. the general procedures);
= Formation of sulfonamides with sulfonyl chlorides;
= Reductive alkylation with carbonyl compounds; or alkylation with alkyl halides, alkylsulfonates or Michael acceptors;
= Formation of ureas by reacting with isocyanates or their equivalents like carbamoyl chlorides or hydroxysuccinimidyl esters;
= Transformation into thioureas with isothiocyanates or their equivalents;
= Carbamate formation by reacting with chloroformates or their surrogates such as hydroxysuccinimidyl carbonates;
= N-arylation to the corresponding N-aryl or N-heteroaryl derivatives with activated aromatic or heteroaromatic halides or sulfonates in the presence of an auxiliary base and/or transition metal catalyst like Pd or Cu catalyst (e.g.
Buchwald-Hartwig coupling).
(ii) Carboxyl group derivatizations like = Amidation with amines in the presence of a coupling reagent;
= Esterification with alcohols.
= Reduction to alcohols (also obtained by reduction of the corresponding esters) (iii) Alcoholic hydroxyl group derivatizations such as = Alkylation to alkyl ethers with alkyl halides or alkylsulfonates, trialkyloxonium tetrafluoroborates;
= Transformation into aryl or heteroaryl ethers by reaction with (a) phenols in the presence of azodicarboxylic acid derivatives and triaryl or trialkyl phosphines (Mitsunobu type reactions); or (b) suitably activated aryl or heteroaryl halides or sulfonates;
= Conversion into carbamates by reaction with isocyanates;
-= Conversion into primary amines (obtained e.g. by hydrogenation of azides, which in turn are prepared by the reaction of an alcohol with DPPA, PPh3, and DEAD) and derivatization of these amines as described above;
= Oxidation to carbonyl compounds, which in turn can be further elaborated by e.g. reductive amination, Wittig reaction or related olefination reactions, etc.;
= Esterification with carboxylic acids or their activated surrogates.
(iv) Aryl halide or sulfonate derivatizations by e.g. Suzuki, Sonogashira, Buchwald, Negishi or Kumada coupling reactions etc.
SW-7: Synthesis workflow for derivatizations of functional groups at the solid phase As a possible alternative to SW-6, macrocyclic compounds I with one or more orthogonally protected exocyclic functional groups and one free primary amino group can be converted into fully derivatized products on solid support as previously described for related macrocyclic compounds (W02011/014973) by:
a7) Attachment of the macrocyclic amine to an appropriately functionalized solid support by reductive amination;
b7) Acylation, carbamoylation, or sulfonylation, of the secondary amine functionality generated in the previous step a7 or conversion of this secondary amine functionality into carbamates;
c7) Removal of the protecting group from the second attachment point;
d7) Derivatization of the liberated second functional group whereby e.g. amino groups can be alkylated or converted into amides, ureas, thioureas carbamates, or sulfonamides; and carboxylic acid moieties can be transformed into amides or esters;
e7) Repetitions of steps c7 and d7 if a third, fourth etc. attachment point is available;
f7) Release of the final product from the solid support.
In case of macrocyclic carboxylic acids the attachment to a polymer-supported amine is followed by derivatizations and release in analogy to c7 to f7:
a8) Attachment of an amine to an appropriately functionalized solid support by reductive amination;
b8) Coupling of the macrocyclic carboxylic acid to the polymer-supported amine of step a8;
c8-f8) Derivatizations and release in analogy to steps c7-f7.
General procedures for synthetic steps utilized in SW-7 The functionalized solid support The solid support (polymer, resin) is preferably a derivative of polystyrene cross-linked with 1-5% divinylbenzene, of polystyrene coated with polyethyleneglycol (Tentage1T'), or of polyacrylamide (D. Obrecht, J.-M. Villalgordo, Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries, Tetrahedron Organic Chemistry Series, Vol. 17, Pergamon 1998). It is functionalized by means of a linker, i.e. an am-bifunctional spacer molecule with an anchoring group for the solid support on one end, and on the other end by means of a selectively cleavable functional group that is used for subsequent transformations and finally for release of the product. For the examples of the present invention linkers are used that release an N-acyl (amide, urea, carbamate) or an N-sulfonyl (sulfonamide) derivative under acidic conditions. These kinds of linkers have been applied in the backbone amide linker (BAL) strategy for solid-phase synthesis of linear and cyclic peptides (K.J. Jensen et al., J. Am. Chem. Soc. 1998, 120, 5452; J. Alsina et al., Chem. Eur. J. 1999, 5, 2787-2795) and heterocyclic compounds as well (T.F. Herpin et al., J. Comb. Chem. 2000, 2, 513-521; M. del Fresno et al., Tetrahedron Lett. 1998, 39, 2639-2642; N.S. Gray et al., Tetrahedron Lett. 1997, 38,1161-1164).
Examples of such functionalized resins include DFPE polystyrene (2-(3,5-dimethoxy-4-formylphenoxy)ethyl polystyrene), DFPEM polystyrene (2-(3,5-dimethoxy-4-formylphenoxy)ethoxymethyl polystyrene), FMPB resins (4-(4-formy1-3-methoxy-phenoxy)butyryl AM-resin), FM PE polystyrene HL (2-(4-formy1-3-methoxyphenoxy) ethyl polystyrene HL), FMPB NovaGelTM (4-(4-formy1-3-methoxyphenoxy)butyryl NovaGel; a PEG PS resin).
Attachment of the macrocyclic amine to the functionalized resin (steps a7 and b7) and subsequent N-acylation or N-sulfonylation The macrocyclic primary amine is attached to the functionalized solid support by reductive amination preferably with NaBH(OAc)3 as reducing agent in 1,2-dichloroethane and in the presence of trimethyl orthoformate or i-Pr2NEt.
The use of reductive aminations for such processes as well as the subsequent N-acylation or N-sulfonylation are well-documented; for example NaBH3CN in DMF
or in methanol, or NaBH(OAc)3 in DMF/acetic acid or in dichloromethane/acetic acid have been used (cf. references cited for the functionalized solid support). The N-acylation is favorably conducted with carboxylic acids in the presence of coupling reagents like PyBOP, PyBroP, or HATU or with carboxylic acid fluorides/ chlorides or carboxylic acid anhydrides.
Deprotection (steps c7) The second attachment point is an Alloc or Fmoc protected amino group or a carboxyl group protected as allyl ester. Standard methods (cf. SW-6) are applied for their deprotection and derivatization.
Release from the resin (step f7) The final products are detached from the solid support by acids dissolved in organic solvents and/or H20. The use of TFA in dichloromethane, of TFA in dichloromethane in the presence of a scavenger such as H20 or dimethyl sulfide, or of TFA/H20 and TFA/H20/dimethylsulfide has been described (cf. references cited for the functionalized solid support).
Attachment of the macrocyclic carboxylic acid to the functionalized resin (steps a8 and b8) A primary amine is attached to the functionalized solid support by reductive amination preferably using NaBH(OAc)3 in 1,2-dichloroethane in the presence of trimethyl orthoformate.
Subsequent acylation with the macrocyclic carboxylic acids is favorably conducted in the presence of coupling reagents like HATU, PyBOP, or PyBroP.
It is worth mentioning that the initially attached primary amine corresponds to an attachment point derivatization of the carboxylic acid.
Properties and usefulness The macrocycles of type I of the present invention interact with specific biological targets. In particular, they show i) inhibitory activity on endothelin converting enzyme of subtype 1 (ECE-1), ii) inhibitory activity on the cysteine protease cathepsin S
(CatS), iii) antagonistic activity on the oxytocin (OT) receptor), iv) antagonistic activity on the thyrotropin-releasing hormone (TRH) receptor), v) agonistic activity on the bombesin 3 (BB3) receptor, vi) antagonistic activity on the leukotriene B4 (LTB4) receptor, and/or vii) antimicrobial activity against at least one bacterial strain, in particular Staphylococcus aureus or Streptococcus pneumoniae.
Accordingly, these compounds are useful for the prevention or treatment of i) diseases resulting from abnormally high plasma or tissue levels of the potent vasoconstrictive peptide endothelin-1 (ET-1), like systemic and pulmonary hypertension, cerebral vasospasm and stroke, asthma, cardiac and renal failure, atherosclerosis, preeclampsia, benign prostatic hyperplasia, and carcinogenesis (S.
De Lombaert et al., J. Med. Chem. 2000, 43, 488-504); ii) a wide range of diseases related to Cathepsin S, including neuropathic hyperalgesia, obesity, and in particular diseases of the immune system, like rheumatoid arthritis (RA), multiple sclerosis (MS), myasthenia gravis, transplant rejection, diabetes, Sjogrens syndrome, Grave's disease, systemic lupus erythematosis, osteoarthritis, psoriasis, idiopathic thrombocytopenic purpura, allergic rhinitis, asthma, atherosclerosis, and chronic obstructive pulmonary disease (COPD) (0. Irie et al., J. Med. Chem. 2008, 51, 5505; W02009/1112826); iii) diseases and conditions associated to an overexpression of oxytocin (OT), like preterm delivery (P. D. Williams, D. J.
Pettibone, Curr. Pharm. Des. 1996, 2, 41-58; A. D. Borthwick, J. Med. Chem. 2010, 53, 6538); iv) diseases related to a dysfunction in the homoestatic system of the thyrotropin-releasing hormone (TRH), such as infantile spasms, generalized and refractory partial seizures, edematous and destructive forms of acute pancreatitis, and certain inflammatory disorders (e.g. autoimmune diseases, inflammatory bowel diseases, cancer-related fatigue or depression, and Alzheimer's disease) (P.-Y. Deng et al., J. Physiot 2006, 497-511; J. Kamath et al., Pharmacol. Ther. 2009, 121, 20-28); v) diseases related to a dysfunction of the bombesin 3 (BB3) receptor, like obesity and impairment of glucose metabolism, disorders of lung development, pulmonary diseases, CNS disorders and carcinogenesis (R. T. Jensen, Pharmacol.

Rev. 2008, 60, 1-42); vi) diseases potentially treatable by blockade of the leukotriene B4 (LTB4) receptor, especially inflammatory and allergic diseases like asthma, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), allergic rhinitis, atopic dermatitis, allergic conjunctivitis, obliterative bronchiolitis after lung transplantation, or interstitial lung diseases (R.A.
Goodnow, Jr., et al., J. Med. Chem. 2010, 53, 3502-3516; E.W. Gelfand et al., H. Ohnishi et., Allergol. mt. 2008, 57, 291-298); and/or vii) a wide range of infections caused by microorganisms, in particular strains of Staphylococcus aureus or Streptococcus pneumonia, comprising infections related to: a) respiratory diseases like cystic fibrosis, emphysema, asthma or pneumonia, b) skin or soft tissue diseases such as surgical wounds, traumatic wounds, burn wounds or herpes, smallpox, rubella or measles, c) gastrointestinal diseases including epidemic diarrhea, necrotizing enterocolitis, typhlitis or gastroenteritis or pancreatitis, d) eye diseases such as keratitis and endophthalmitis, e) ear diseases, e.g. otitis, f) CNS diseases including brain abscess and meningitis or encephalitis, g) bone diseases such as osteochondritis and osteomyelitis, h) cardiovascular diseases like endocartitis and pericarditis, or i) genitourinal diseases such as epididymitis, prostatitis and urethritis (R.P. Rennie, Handb. Exp. PharmacoL 2012, 211, 45-65; W. Bereket et al., Eur.
Rev.
Med. PharmacoL Sci. 2012, 16, 1039-1044; D.P. Calfee, Curr. Opin. Infect. Dis.
2012, 25, 385-394). Additional uses of antimicrobial macrocycles of type I comprise the treatment or prevention of microbial infections in plants and animals or as disinfectants or preservatives for materials such as foodstuff, cosmetics, medicaments and other nutrient-containing materials.
The macrocycles, as such or after further optimization, may be administered per se or may be applied as an appropriate formulation together with carriers, diluents or excipients well-known in the art.
When used to treat or prevent the diseases mentioned above the macrocycles can be administered singly, as mixtures of several macrocycles, or in combination with other pharmaceutically active agents. The macrocycles can be administered per se or as pharmaceutical compositions.
Pharmaceutical compositions comprising macrocycles of the invention may be manufactured by means of conventional mixing, dissolving, granulating, coated tablet-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries which facilitate processing of the active macrocycles into preparations which can be used pharmaceutically. Proper formulation depends upon the method of administration chosen.
For topical administration the macrocycles of the invention may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art.
Systemic formulations include those designed for administration by injection, e.g.
= subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral or pulmonary administration.
For injections, the macrocycles of type I may be formulated in adequate solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. The solutions may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the = macrocycles of the invention may be in powder form for combination with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation as known in the art.
For oral administration, the compounds can be readily formulated per se or by combining the active macrocycles of the invention with pharmaceutically acceptable carriers well known in the art. Such carriers enable the macrocycles of type I
to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions etc., for oral ingestion by a patient to be treated. For oral formulations such as, for example, powders, capsules and tablets, suitable excipients include fillers such as sugars, (e.g. lactose, sucrose, mannitol or sorbitol) or such as cellulose preparations (e.g. maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose); and/or granulating agents; and/or binding agents such as polyvinylpyrrolidone (PVP). If desired, desintegrating agents may be added, such as cross-linked polyvinylpyrrolidones, agar, or alginic acid or a salt thereof, such as sodium alginate. Solid dosage forms may be sugar-coated or enteric-coated using standard techniques.
For oral liquid preparations such as, for example, suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, glycols, oils, alcohols, etc. In addition, flavoring agents, preservatives, coloring agents and the like may be added.
For buccal administration, the composition may take the form of tablets, lozenges, etc. formulated as usual.
For administration by inhalation, the macrocycles of the invention are conveniently delivered in form of an aerosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. hydrofluoroalkanes (HFA) such as HFA 134a (1,1,1,2,-tetrafluoroethane); carbon dioxide or another suitable gas. In the case of a pressurized aerosol the dose unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the macrocycles of the invention and a suitable powder base such as lactose or starch.
The compounds may also be formulated in rectal or vaginal compositions such as suppositories together with appropriate suppository bases like cocoa butter or other glycerides.
In addition to the formulations described above, the macrocycles of the invention may also be formulated as depot preparations. Such slow release, long acting formulations may be administered by implantation (e.g. subcutaneously or intramuscularly) or by intramuscular injection. For the manufacture of such depot preparations the macrocycles of the invention may be formulated with suitable polymeric or hydrophobic materials (e.g. as an emulsion in an acceptable oil) or with ion exchange resins, or as sparingly soluble salts.
Furthermore, other pharmaceutical delivery systems may be employed such as liposomes and emulsions. Certain organic solvents such as dimethylsulfoxide may also be employed. Additionally, the macrocycles of type I may be delivered using a sustained-release system, such as semi-permeable matrices of solid polymers containing the therapeutic agent. Various sustained-release materials have been established and are well-known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds over a period of a few days up to several months. Depending on the chemical nature and the biological stability of the therapeutic agent, additional strategies for stabilization may be employed.
As the macrocycles of the invention may contain charged residues, they may be included in any of the above-described formulations as such or as pharmaceutically acceptable salts. Pharmaceutically acceptable salts tend to be more soluble in aqueous and other protic solvents than the corresponding free base or acid forms.
The macrocycles of the invention, or compositions thereof, will generally be used in an amount effective to achieve the intended purpose. It is understood that the amount used will depend on a particular application.
For example, the therapeutically effective dose for systemic administration can be estimated initially from in vitro assays: A dose can be formulated in animal models to achieve a circulating macrocycle concentration range that includes the IC50 or as determined in the cell culture (i.e. the concentration of a test compound that shows half maximal inhibitory concentration in case of antagonists or half maximal effective concentration in case agonists). Such information can be used to more accurately determine useful doses in humans.
Initial dosages can also be determined from in vivo data, e.g. animal models, using techniques that are well known in the art.
Dosage amounts for applications such as gastroparesis or schizophrenia etc.
may be adjusted individually to provide plasma levels of the active compound that are sufficient to maintain the therapeutic effect. Therapeutically effective serum levels may be achieved by administering multiple doses each day.
In cases of local administration or selective uptake, the effective local concentration of the macrocycles of the invention may not be related to plasma concentration.
Those having the ordinary skill in the art will be able to optimize therapeutically effective dosages without undue experimentation.
The amount of macrocycle administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the method of administration and the judgment of the prescribing physician.
Normally, a therapeutically effective dose of the macrocycles described herein will provide therapeutic benefit without causing substantial toxicity.
Toxicity of the macrocycles can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD50 (the dose lethal to 50% of the population) or the LID100 (the dose lethal to 100%
of the population). The dose ratio between toxic and therapeutic effect is the therapeutic index. Compounds which exhibit high therapeutic indices are preferred. The data obtained from cell culture assays and animal studies can be used in formulating a dosage range that is not toxic for use in humans. The dosage of the macrocycles of the invention lies preferably within a range of circulating concentrations that include the effective dose with little or no toxicity. The dosage may vary within the range depending upon the dosage form and the route of administration. The exact formulation, route of administration and dose can be chosen by the individual physician in view of the patient's condition (cf. E. Fingl et al. in L.
Goodman und A.
Gilman (eds), The Pharmacological Basis of Therapeutics, 5th ed. 1975, Ch.1, p.1).
Another embodiment of the present invention may also include compounds, which are identical to the compounds of formula I, except that one or more atoms are replaced by an atom having an atomic mass number or mass different from the atomic mass number or mass usually found in nature, e.g. compounds enriched in (D), 3H, 11C, 14C, 1251 etc. These isotopic analogs and their pharmaceutical salts and formulations are considered useful agents in therapy and/or diagnostics, for example, but not limited to, fine-tuning of in vivo half-life.

Examples The following examples illustrate the invention in more detail but are not intended to limit its scope in any way. Before specific examples are described in detail the used abbreviations and applied general methods are listed.
Ac: acetyl addn: addition ADDP: azodicarboxylic dipiperidide Alloc: allyloxycarbonyl AllocCI: allyl chloroformate Alloc0Su: allyloxycarbonyl-N-hydroxysuccinimide AM-resin: aminomethyl resin AM-PS: aminomethyl polystyrene aq.: aqueous arom.: aromatic Bn: benzyl BOP: (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate Boc: tert-butoxycarbonyl br.: broad Cbz: benzyloxycarbonyl CbzCI: benzyl chloroformate Cbz0Su: N-(benzyloxycarbonyloxy)succinimide Cl-HO Bt: 6-chloro-1-hydroxybenzotriazole CMBP: cyanomethylenetributyl-phosphorane m-CPBA: 3-chloroperbenzoic acid d: day(s) or doublet (spectral) DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DCE: 1,2-dichloroethane DEAD: diethyl azodicarboxylate DFPE polystyrene: 2-(3,5-dimethoxy-4-formylphenoxy)ethyl polystyrene DIAD: diisopropyl azodicarboxylate DIC: N,N'-diisopropylcarbodiimide DMAP: 4-(dimethylamino)pyridine DME: 1,2-dimethoxyethane DMF: dimethylformamide DMSO: dimethyl sulfoxide DPPA: diphenyl phosphoryl azide DVB: divinylbenzene EDC: 143-(dimethylamino)propy11-3-ethylcarbodiimide equiv.: equivalent Et: ethyl Et3N: triethylamine Et20: diethyl ether Et0Ac: ethyl acetate Et0H: ethanol exp.: experimental FC: flash chromatography FDPP: pentafluorophenyl diphenylphosphinate Fl-MS: flow injection mass spectrometry Fmoc: 9-fluorenylmethoxycarbonyl Fmoc-CI: Fmoc chloride, 9-fluorenylmethyl chloroformate Fmoc-OSu: (9H-fluoren-9-yl)methyl 2,5-dioxopyrrolidin-1-ylcarbonate (or 9-fluorenylmethyl-succinimidyl carbonate) h: hour(s) HATU: 0-(7-azabenzotriazol-1-y1)-N,N,M,N'-tetramethyluronium hexa-fluorophosphate HBTU: 0-(benzotriazol-1-y1)-N,N,N',W-tetramethyluronium hexafluorophosphate mCPBA: 3-chloroperbenzoic acid HCTU: 0-(6-chlorobenoztriazol-1-y1)-N,N,NW-tetramethyluronium hexafluorophosphate HFIP: Hexafluoroisopropanol (1,1,1,3,3,3-hexafluoro-2-propanol) HL: high loading HOAt: 1-hydroxy-7-azabenzotriazole HOBt.H20: 1-hydroxybenzotriazole hydrate HMPA: hexamethylphosphoramide i.v.: in vacuo m: multiplet (spectral) MeCN: acetonitrile MeOH: methanol Me: methyl NM P: 1-methy1-2-pyrrolidinone Ns: 2-nitrobenzenesulfonyl; 4-nitrobenzenesulfonyl PdC12(PPh3)2: bis(triphenylphosphine)palladium (II) dichloride Pd(dppf)C12-CH2C12: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane Pd(PPh3)4: tetrakis(triphenylphosphine)palladium(0) PEG PS resin: polyethyleneglycol coated polystyrene resin PG: protective group Ph: phenyl PPh3: triphenylphosphine prep.: preparative i-Pr: isopropyl i-Pr2NEt: N-ethyl-N,N-diisopropylamine i-PrOH: isopropanol PyBOP: (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate PyBroP: bromotripyrrolidinophosphonium hexafluorophosphate PyClu: N,N,N',N'-bis-(tetramethylene)-chloroforamidinium hexafluorophosphate q: quartet (spectral) quant.: quantitative quint : quintet (spectral) rt: room temperature s : singlet (spectral) sat.: saturated soln: solution TBAF : tetrabutylammonium fluoride t: triplet (spectral) Teoc: 2-(trimethylsilyl)ethoxycarbonyl tert.: tertiary TFA: trifluoroacetic acid THF: tetrahydrofuran TLC: thin layer chromatography TMAD: tetramethylazodicarboxamide T3P = T3PTm: propanephosphonic acid cyclic anhydride p-Ts0H: p-toluenesulfonic acid Umicore M72 SIMes (RD): [1,3-bis(2,4,6-trimethylpheny1)-2-imidazolidinylidene]dichloro-[(2-isopropoxy)(5-pentafluorobenzoylamino)benzylidene]ruthenium(II) General Methods TLC: Merck (silica gel 60 F254, 0.25 mm).
Flash chromatography (FC): Fluka silica gel 60 (0.04-0.063 mm) and Interchim Puriflash IR 60 silica gel (0.04-0.063 mm).
I. Analytical HPLC-MS methods:
Rt in min (purity at 220 nm in %), m/z [M-1-1-1]+
UV wave length 220 nm, 254 nm MS: Electrospray Ionization Volume of injection: 5 pL
Method LC-MS: Agilent HP1100 (DAD detector) Column: Ascentis EXPreSSTM C18 2.7 pm, 3x50 mm (53811U ¨ Supelco Inc.) Mobile Phases: A: 0.1% TFA in Water; B: 0.085% TFA in MeCN
Column oven temperature: 55 C
Gradient:
Time Flow %A %B
[min.] [mUmin]
0 1.3 97 3 0.05 1.3 97 3 2.95 1.3 3 97 3.15 1.3 3 97 3.17 1.3 97 3 3.2 1.3 97 3 Method la: MS scan range: 95 ¨ 1800 Da; centroid mode, positive mode 40V, scan time: 1 sec Method lb: MS scan range: 95 ¨800 Da; centroid mode, positive mode 40V, scan time: 1 sec Method lc: MS scan range: 95 ¨ 1800 Da; centroid mode, positive mode 20V, scan time: 1 sec Method Id: MS scan range: 95¨ 1800 Da; profile mode, positive mode 40V, scan time: 1 sec Method le: MS scan range: 95¨ 1800 Da; profile mode, positive mode 80V, scan time: 1 sec Method If: MS scan range: 95¨ 1800 Da; profile mode, positive mode 20V, scan time: 1 sec Method 1g: MS scan range: 95¨ 1800 Da; centroid mode, positive mode 80V, scan time: 1 sec Method 2 LC-MS: Agilent HP1100 (DAD detector) Column: Ascentis ExpressTm C18 2.7 pm, 3x50 mm (53811U ¨ Supelco Inc.) Mobile Phases: A: Ammonium Bicarbonate 1 mM in Water¨ pH=10 in Water; B:
MeCN
Column oven temperature: 55 C
Gradient:
Time Flow %A %B
[min.] [mUmin]
0 1.3 97 3 0.05 1.3 97 3 2.95 1.3 3 97 3.15 1.3 3 97 3.17 1.3 97 3 3.2 1.3 97 3 Method 2a: MS scan range: 95 ¨ 800 Da; centroid mode, negative mode 40V
scan time: 1 sec Method 2b: MS scan range: 95 ¨ 1800 Da; centroid mode, negative mode 40V
scan time: 1 sec Method 2c: MS scan range: 95 ¨ 1800 Da; centroid mode, positive mode 40V
scan time: 1 sec Method 2d: MS scan range: 95¨ 1800 Da; centroid mode, positive mode 20V
scan time: 1 sec Method 2e: MS scan range: 95¨ 800 Da; centroid mode, positive mode 40V
scan time: 1 sec Method 2f: MS scan range: 95¨ 1800 Da; profile mode, positive mode 40V
scan time: 1 sec Method 3 LC-MS: Dionex Ultimate 3000 RS (DAD detector) Column: Ascentis ExpressTm C18 2.7 pm, 2.1x50 mm (53822-U ¨ Supelco Inc.) Mobile Phases: A: 0.1% TFA in Water; 6: 0.085% TFA in MeCN
Column oven temperature: 55 C
Gradient:
Time Flow %A %B
[min.] [mUmin]
0 1.4 97 3 0.05 1.4 97 3 1.95 1.4 3 97 2.15 1.4 3 97 2.18 1.4 97 3 2.3 1.4 97 3 Method 3a: MS scan range: 95¨ 1800 Da; centroid mode, positive mode 40V
scan time: 1 sec Method 3b: MS scan range: 95¨ 1800 Da; profile mode, positive mode 40V
scan time: 1 sec Method 4 LC-MS: Agilent HP1100 (DAD detector) Column: Ascentis ExpressTM F5 2.7 pm, 3x50 mm (53576-U ¨ Supelco Inc.) Mobile Phases: A: 0.1%TFA in Water; B: 0.085% TFA in MeCN
Column oven temperature: 55 C
Method 4a and method 4b Gradient:
Time Flow %A %B
[min.] [mL/min]
0 1.3 70 30 0.05 1.3 70 30 2.95 1.3 30 97 3.15 1.3 30 97 3.17 1.3 70 30 3.2 1.3 70 30 Method 4a: MS scan range: 95¨ 1800 Da; centroid mode, positive mode 40V, scan time: 1sec Method 4b: MS scan range: 95¨ 1800 Da; profile mode, positive mode 40V, scan time: 1sec Method 4c Gradient:
Time Flow %A %B
[min] [mUmin]
0 1.3 97 3 0.05 1.3 97 3 2.95 1.3 3 97 3.15 1.3 3 97 3.17 1.3 97 3 3.2 1.3 97 3 Method 4c: MS scan range: 95 ¨ 1800 Da; centroid mode, positive mode 20V, scan time: 1sec Method 5 LC-MS: Agilent HP1100 (DAD detector) Column: AtlantisTm T3 3 pm, 2.1x50 mm (186003717 ¨ Waters AG) Mobile Phases: A: 0.1% TFA in Water; B: 0.085% TFA in MeCN
Column oven temperature: 55 C
Gradient:
Time Flow %A %B
[min.] [mUmin]
0 0.8 100 0 0.1 0.8 100 0 2.9 0.8 50 50 2.95 0.8 3 97 3.2 0.8 3 97 3.22 0.8 100 100 3.3 0.8 100 100 Method 5a: MS scan range: 95¨ 1800 Da; centroid mode, positive mode 40V, scan time: 1sec II. Preparative HPLC methods:
1. Reverse Phase ¨ Acidic conditions Method la Column: XBridgeTM C18 5 pm, 30 x 150 mm (Waters AG) Mobile phases:
A: 0.1% TFA in Water/Acetonitrile 98/2 v/v 8:0.1% TFA Acetonitrile Method lb Column: XBridgeTm C18 5 pm, 30 x 100 mm (Waters AG) Mobile phases:
A: 0.1% TFA in Water/Acetonitrile 98/2 v/v 8:0.1% TFA Acetonitrile Method lc Column: GeminiNXTM C18 5 pm, 30 x 100 mm (Phenomenex Inc.) Mobile phases:
A: 0.1% TFA in Water/Acetonitrile 98/2 v/v .5: 0.1% TFA Acetonitrile Method Id Column: XBridgeTM Prep C18 10 pm, 50 x 250 mm (Waters AG) Mobile phases:
A: 0.1% TFA in Water/Acetonitrile 98/2 v/v B: Acetonitrile Flow rate: 150 mL/min 2. Reverse Phase - Basic conditions Method 2a Column: XBridgeTM C18 5 pm, 30 x 150 mm (Waters AG) Mobile phases:
A: 10 mM Ammonium Bicarbonate pH 10/Acetonitrile 98/2 v/v B: Acetonitrile Method 2b Column: XBridgeTM C18 5 pm, 30 x 100 mm (Waters AG) Mobile phases:
A: 10 mM Ammonium Bicarbonate pH 10/Acetonitrile 98/2 v/v B: Acetonitrile 3. Normal Phase Method 3 Column: VP 100/21 NUCLEOSILTm 50-10, 21 x 100 mm (Macherey-Nagel AG) Mobile phases: A: Hexane B: Ethylacetate C: Methanol Fl-MS: Agilent HP1100; m/z [M+H]+
NMR Spectroscopy: Bruker Avance 300, 11-I-NMR (300 MHz) in the indicated solvent at ambient temperature. Chemical shifts 6 in ppm, coupling constants J in Hz.
Specific Examples In the examples below and if no other sources are cited, leading reference for standard conditions of protecting group manipulations (protection and deprotection) are 1) P.G.M.
Wuts, T.W. Greene, Greene's Protective Groups in Organic Synthesis, John Wiley and Sons, 4th Edition, 2006; 2) P.J. Koncienski, Protecting Groups, 3rd ed., Georg Thieme Verlag 2005; and 3) M. Goodman (ed.), Methods of Organic Chemistry (Houben-Weyl), Vol E22a, Synthesis of Peptides and Peptidomimetics, Georg Thieme Verlag 2004.
Starting materials Template A building blocks (Scheme 5):
3'-Hydroxybipheny1-2-carboxylic acid (1) is commercially available.
Methyl 3'-hydroxybipheny1-2-carboxylate (2) Thionyl chloride (7.7 mL, 105 mmol) was added at 0 C to a soln of 1 (4.5 g, 21.0 mmol) in Me0H (55 mL). The mixture was stirred for 10 min at 0 C and then heated to reflux for 4 h. Evaporation of the volatiles, aqueous workup (Et0Ac, sat.
aq.
NaHCO3 soln; Na2SO4) and FC (hexane/Et0Ac 5:1) afforded the ester 2 (4.34 g, 90%).
Data of 2: C14H1203 (228.2). 1H-NMR (DMSO-d6): 9.52 (br. s, OH); 7.68 (dd, J =
1.1, 7.6, 1 H); 7.59 (dt, J = 1.5, 7.6, 1 H); 7.47 (dt, J = 1.3, 7.5, 1 H); 7.40 (dd, J = 0.9, 7.6, 1 H); 7.20 (t-like m, J = 8.0, 1 H); 6.75 (m, 1 H); 6.70 ¨ 6.67 (m, 2 H); 3.59 (s, 3 H).

2'-Hydroxybipheny1-3-carboxylic acid (3) is commercially available.
Methyl 2'-hydroxybipheny1-3-carboxylate (4) Thionyl chloride (6.8 mL, 93 mmol) was added at 0 C to a soln of 3 (4.0 g, 18.6 mmol) in Me0H (60 mL). The mixture was stirred for 10 min at 0 C and then heated to reflux for 3 h. Evaporation of the volatiles and aqueous workup (Et0Ac, sat. aq.
NaHCO3 soln; Na2SO4) afforded the ester 4 (3.68 g, 86%).
Data of 4: C14H1203 (228.2). LC-MS (method 2a): Rt = 1.95 (98), 226.9 ([M-H]-). 1H-NMR (DMSO-d6): 9.66 (s, 1 H); 8.16 (t, J = 1.6, 1 H); 7.89 (d-like m, 1 H);
7.81 (d-like m, 1 H); 7.56 (t, J = 7.7, 1 H); 7.29 (dd, J = 1.7, 7.6, 1 H); 7.20 (t-like m, 1 H); 6.98 -6.88 (m, 2 H); 3.87 (s, 3 H).
2'-Hydroxy-5'-methoxybipheny1-3-carboxylic acid (5) is commercially available.
Methyl 2'-hydroxy-5'-methoxybipheny1-3-carboxylate (6) Thionyl chloride (5.14 mL, 71 mmol) was added at 0 C to a soln of 5 (5.74 g, 23.5 mmol) in Me0H (100 mL). The mixture was heated to reflux for 2 h. Evaporation of the volatiles, aqueous workup (Et0Ac, sat. aq. NaHCO3 soln; Na2SO4) and FC
(hexane/Et0Ac 4:1) afforded the ester 6 (5.1 g, 84%).
Data of 6: C15H1404 (258.3). 1H-NMR (DMSO-d6): 9.18 (s, OH); 8.17 (t, J = 1.7, 1 H);
7.89 (td, J = 1.4, 7.8, 1 H); 7.82 (td, J = 1.5, 8.0, 1 H); 7.56 (t, J = 7.8, 1 H); 6.91 -6.78 (m, 3 H); 3.87 (s, 3 H); 3.72 (s, 3 H).
3'-Hydroxybipheny1-3-carboxylic acid (7) is commercially available.
Methyl 3'-hydroxybipheny1-3-carboxylate (8) Thionyl chloride (4.1 mL, 56 mmol) was added at 0 C to a soln of 7 (4.0 g, 18.6 mmol) in Me0H (160 mL). The mixture was heated to reflux for 2 h. Evaporation of the volatiles, filtration of the residue through a pad of silica gel (Et0Ac) and FC
(hexane/Et0Ac 93:7 to 0:100) afforded the ester 8 (4.0 g, 94%).
Data of 8: C14E11203 (228.2). LC-MS (method 2a): Rt = 1.90 (98), 227.3 ([M-H1-). 1H-NMR (DMSO-d6): 9.63 (br. s, OH); 8.13 (t, J = 1.6, 1 H); 7.96 - 7.88 (m, 2 H), 7.61 (t, J = 7.7, 1 H); 7.29 (t, J = 7.8, 1 H); 7.10 (m, 1 H); 7.06 (t, J = 2.0, 1 H);
6.81 (m, 1 H);
3.89 (s, 3 H).

5-(3-Hydroxyphenyl)nicotinic acid (9) is commercially available.
5-(3-Acetoxyphenyl)nicotinic acid (10) At 0 C acetic anhydride (18.8 mL, 0.2 mol) was added dropwise to a soln of 5-(3-hydroxyphenyl)nicotinic acid (9; 7.13 g, 0.033 mol) in 4 M aq. NaOH soln (41.4 mL, 0.166 mol). The mixture was stirred for 1 h. A precipitate was formed. The mixture was diluted with 4 M aq. NaOH soln (41.4 mL, 0.166 mol). More acetic anhydride (18.8 mL, 0.2 mol) was added and stirring was continued for 2 h followed by the addition of H20 (50 mL). The mixture was acidified to pH 1 by addition of 3 M
aq. HCI
soln. The solid was filtered, washed (H20) and dried i.v. to afford 10 HCI
(8.22 g, 84%).
Data of 10.HCI: C14H11N04.HCI (257.2, free base). LC-MS (method 1b): R1 = 1.22 (99), 258.0 ([M+H]+). 1H-NMR (DMSO-d6):13.62 (very br. s, 1 H); 9.12 (d, J =
2.0, 1 H); 9.07 (d, J = 1.3, 1 H); 8.46 (s, 1 H); 7.71 (d, J = 7.7, 1 H); 7.63 (s, 1 H); 7.57 (t, J =
7.9, 1 H); 7.23 (d, J = 8.0, 1 H); 2.31 (s, 3 H).
2-Bromothiophenol (11) is commercially available.
3-Hydroxyphenylboronic acid (12) is commercially available.
5-Bromopyridine-3-thiol (13) was prepared as described in the literature (S.A.

Thomas et al. Bioorg. Med. Chem. Lett. 2006, 16, 3740 ¨ 3744).
2-Hydroxyphenylboronic acid (14) is commercially available.
4-(3-Hydroxypyridin-2-yl)benzoic acid (92) is commercially available.
Methyl 4-(3-hydroxypyridin-2-yl)benzoate (93) Thionyl chloride (7.6 mL, 104 mmol) was added at 4 C to a soln of 92 (4.5 g, 21.0 mmol) in Me0H (130 mL). The mixture was heated to 70 C for 14 h and concentrated. The residue was dissolved in CHCI3 (200 mL) and Et0H (20 mL) and treated with aq. NaHCO3 soln (100 mL). The organic phase was separated, the aq.
phase was extracted repeatedly with CHCI3. The combined organic phases were dried (Na2SO4), filtered and concentrated to afford the ester 93 (4.45 g, 92%).

Data of 93: C13H111\103 (229.2). LC-MS (method 1a): Rt = 1.07 (90), 230.1 ([M+H]).
1H-NMR (DMSO-d6): 10.40 (br. s, OH), 8.32 - 8.18 (m, 3 H); 8.02 (d, J = 8.6, 2 H), 7.38 (dd, J = 1.4, 8.2, 1 H); 7.26 (dd, J = 4.4, 8.2, 1 H); 3.88 (s, 3 H).
4-(3-Fluoro-5-hydroxyphenyl)thiophene-2-carboxylic acid (98) At rt, a solution of tert-butyl 2,2,2-trichloroacetimidate (27.7 mL, 155 mmol) in CH2Cl2 (50 mL) was added dropwise to a soln of 4-bromothiophene-2-carboxylic acid (94;

16.0 g, 77.3 mmol) in CH2Cl2 (150 mL). The mixture was stirred for 16 h. A
precipitate was formed, which was removed by filtration. The filtrate was concentrated. FC
(hexane/Et0Ac 99:1 to 97:3) yielded 95 (18.7 g, 92%).
Sat. aq. NaHCO3 soln (183 mL) was added to a soln of 95 (17.2 g, 65.2 mmol), 3-fluoro-5-hydroxyphenylboronic acid (96; 15.3 g, 97.9 mmol) and Pd(PPh3)4 (3.77 g, 3.26 mmol) in dioxane (517 mL). The mixture was heated to reflux for 2 h.
Aqueous workup (Et0Ac, sat. aq. Na2CO3 soln, sat. aq. Neel soln; Na2SO4) and FC
(hexane/Et0Ac 90:10) afforded 97 (12.55 g, 65%).
TFA (150 mL) was added at rt to a mixture of 97 (12.5 g, 42.6 mmol) in CH2Cl2 (150 mL). The soln was stirred for 2.5 h and concentrated to give 98 (10.3 g, quant. yield).
Data of 98: C11H7F035 (238.2). 1H-NMR (DMSO-c16): 13.23 (br. s, 1 H); 10.03 (br. s, 1 H); 8.21 (d, J = 1.6, 1 H); 8.05 (d, J = 1.6, 1 H); 7.05 (m, 1 H); 6.95 (t, J
= 1.7, 1 H), 6.53 (td, J = 2.2, 10.7, 1 H).
3-(Allyloxy)-N-methoxy-N-methylthiophene-2-carboxamide (102) At 0 C, ally! bromide (18.1 mL, 209 mmol) was added dropwise to a mixture of 3-hydroxythiophene-2-carboxylic acid (99; 10.0 g, 69.8 mmol) and K2CO3 (48.2 g, mmol) in DMF (255 mL). The mixture was allowed to stir for 2 h at 0 C to rt.
The mixture was filtered and the residue was washed with Et0Ac. The filtrate was concentrated, followed by an aqueous workup (Et20, 1 M aq. HCI soln, sat. aq.
NaHCO3 soln, H20; Na2SO4) to give ester 100 (15.5 g).
At rt, 2 M aq. LiOH soln (346 mL, 691 mmol) was added to a soln of the crude ester 100 (15.5 g) in DME (315 mL). The mixture was heated to 50 C for 16 h and concentrated. The residue was distributed between H20 and Et0Ac. The aqueous phase was acidified with 1 M aq. HCI soln and repeatedly extracted with Et0Ac.
The combined organic layer was dried (Na2SO4), filtered and concentrated to afford the acid 101 (11.5 g, 90%).
At 5 C, i-Pr2NEt (42.3 mL, 249 mmol) was added dropwise to a mixture of 101 (11.45 g, 62.2 mmol), N,0-dimethylhydroxylamine hydrochloride (7.28 g, 74.6 mmol), EDC.HCI (14.3 g, 74.6 mmol), HOBt-I-120 (11.4 g, 74.6 mmol) and DMAP (1.52 g, 12.4 mmol) in DMF (116 mL). The mixture was allowed to warm to rt over 5 h followed by an aqueous workup (Et0Ac, 1 M aq. HCI soln; Na2SO4) and FC
(hexane/Et0Ac 2:1) to afford 102 (9.69 g, 69%).
Data of 102: C10H13NO3S (227.3). LC-MS (method 1c): Rt = 1.59 (92), 228.1 ([11/1+Hy).
tert-Butyl 3-(3-hydroxythiophen-2-yI)-1-methyl-1H-pyrazole-5-carboxylate (106) n-Butyllithium (1.6 M in hexane; 41.9 mL, 67.0 mmol) was added dropwise within min at -55 to -50 C to a soln of tert-butyl propiolate (103; 8.76 mL, 63.8 mmol) in dry THF (200 mL). The mixture was allowed to stir at -40 C for 1.5 h. The mixture was cooled to -78 C. A soln of 102 (7.25 g, 31 9 mmol) in THF (66 mL) was added within 10 min with the temperature not exceeding -64 C. The mixture was stirred for 0.5 h at -78 C, then warmed to -40 C and allowed to slowly warm to 0 C over 3 h. The mixture was poured into 1M aq. KHSO4 soln and extracted with Et0Ac. The organic phase was dried (Na2SO4) and concentrated. FC (hexane/Et0Ac 90:10 to 70:30) afforded the ketone 104 (8.34 g, 89%).
Methylhydrazine (1.0 mL, 18.8 mmol) was added at rt to a soln of 104 (4.6 g, mmol) in Et0H (62 mL). Stirring was continued for 1 h and the volatiles were evaporated. Aqueous workup (Et0Ac, sat. aq. NaHCO3 soln; Na2SO4) and FC
(hexane/Et0Ac 90:10) gave pyrazole 105 (4.25 g, 84%).
Data of 105: C16H20N2035 (320.4). LC-MS (method 4a): R = 1.80 (96), 321.2 ([M+H]-). 1H-NMR (DMSO-d6): 7.40 (d, J = 5.5, 1 H); 7.08 (s, 1 H); 7.07 (d, J
ca 5.9, 1 H); 6.06 (m, 1 H); 5.43 (qd, J = 1.7, 17.3, 1 H); 5.29 (qd, J = 1.6, 10.6, 1 H); 4.69 (td, J = 1.6, 5.0, 2 H); 4.05 (s, 3 H); 1.55 (s, 9 H).
Phenylsilane (15.0 mL, 121 mmol) was added to a soln of 105 (7.75 g, 24 mmol) and Pd(PPh3)4 (1.4 g, 1.2 mmol) in THF (78 mL). The mixture was stirred at rt for 16 h.
More Pd(PPh3)4 (0.8 g, 0.7 mmol) and phenylsilane (6.0 mL, 48 mmol) were added and stirring was continued for 24 h. The volatiles were evaporated followed by an aqueous workup (Et0Ac, 1 M NH4CI soln) and FC (hexane/Et0Ac 90:10) to yield (5.75 g, 84%).
Data of 106: C13H16N2035 (280.3). LC-MS (method la): Rt = 2.40 (94), 281.2 ([M+Hy). 1H-NMR (DMSO-d6): 10.01 (br. s, 1 H); 7.24 (d, J = 5.3, 1 H); 7.04 (s, 1 H);
6.72 (d, J = 5.3, 1 H); 4.04 (s, 3 H); 1.55 (s, 9 H).

2-(4-Hydroxy-3-nitrophenyI)-6-methylpyrimidine-4-carboxylic acid (110) Sat. aq. Na2CO3 soln (52.5 mL) was added to a soln of methyl 2-chloro-6-methylpyrimidine-4-carboxylate (107; 5.0 g, 26.8 mmol), 4-methoxy-3-nitrophenylboronic acid (108; 6.86 g, 34.8 mmol) and PdC12(PPh3)2 (0.94 g, 1.3 mmol) in dioxane (175 mL). The mixture was heated to reflux for 4 h and partially concentrated, followed by an aqueous workup (Et0Ac, 1 M aq. HCI soln; sat. aq.

NaCI soln; Na2SO4). The crude product was suspended in CH2C12/Me0H 2:1; the solid was filtered, washed (Me0H) and dried i.v to afford 109.HCI (3.7 g, 42%). The filtrate was concentrated and purified by FC (CH2C12/Me0H 100:0 to 70:30) to give 109-HCI (3.87g, 44%).
A mixture of 109 HCI (7.5 g, 23.1 mmol) and LiCI (4.9 g, 11.5 mmol) in DMF
(100 mL) was heated to 145 C for 18 h. The volatiles were mostly evaporated. The residue was cooled to 0 C and treated with 1 M aq. HCI soln (250 mL). The resulting suspension was sonicated and filtered. The solid material was washed (Et20) and dried. The solid material was suspended in CH2C12/Et20 1:4, filtered and dried to give 110.HCI (6.5g, 80%).
Data of 110 HCI: C12H9N305-1-1C1 (free base, 275.2). LC-MS (method la): Rt =
1.73 (83), 276.0 ([M+H]+). 1H-NMR (DMSO-d6): 8.91 (d, J = 1.9, 1 H); 8.56 (dd, J =
1.9, 8.8, 1 H); 7.80 (s, 1 H); 7.30 (d, J = 8.8, 1 H); 2.63 (s, 3 H).
2-lodophenol (111) is commercially available.
2-(Ethoxycarbonyl)phenylboronic acid (112) is commercially available.
Ethyl 2-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)benzoate (113) is comercially available.
4-(3-Hydroxypheny1)-2-(trifluoromethyl)oxazole-5-carboxylic acid (117) The aminoacrylic acid ester 115 was prepared according to J.H. Lee et al, J.
Org.
Chem. 2007, 72,10261.
The 2-(trifluoromethyl)oxazole 116 was prepared as described by F. Zhao et al.
J.
Org. Chem. 2011, 76, 10338 for simlar compounds:
A degassed soln of 115 (2.15 g, 9.72 mmol) in DCE (500 mL) was warmed to 45 C.

[Bis(trifluoroacetoxy)iodolbenzene (5.02 g, 11.67 mmol) was added in one portion, and stirring at 45 C was continued for 16 h. Evaporation of the volatiles and FC
(hexane/Et0Ac 98:2) afforded 116 (1.55g, 50%).

Data of 116: C14H12F3N04 (315.2). 1H-NMR (DMSO-d6): 7.62 - 7.57 (m, 2 H); 7.45 (t, J = 8.0,1 H); 7.11 (m, 1 H); 4.38 (q, J = 7.1,2 H); 3.81 (s, 3 H); 1.31 (t, J
= 7.1,3 H).
At 0 C, BBr3 (1 M in THF; 24.2 mL, 24.2 mmol) was added dropwise to a soln of (1.5 g, 4.85 mnnol) in CH2Cl2 (3.5 mL). The mixture was stirred for 16 h at 0 C to rt, slowly added onto ice-cold water (500 mL) and extracted with Et0Ac. The organic phase was washed (sat. aq. NaCl soln), dried (Na2SO4), filtered and concentrated.
FC (hexane/Et0Ac 75:25 to 0:100, then CH2C12/Me0H 90:10) afforded 117 (1.24 g, 95%).
Data of 117: C11H6F3N04 (273.2). 1H-NMR (DMSO-d6): 9.54 (br. s, 1 H), 7.71 -7.65 (m, 2 H); 7.23 (t, J = 7.9, 1 H); 6.80 (m, 1 H).
Modulator B building blocks (Scheme 6):
tert-Butyl (3S,5S)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate hydrochloride (15 HCI) is commercially available.
(2S,4S)-Ally1 4-(tert-butoxycarbonylamino)-2-(hydroxymethyl)-pyrrolidine-1-carboxy-late (16) was prepared by Alloc protection of the secondary amino group of 15.HCI
with allyl chloroformate in CH2Cl2 in the presence of aq. NaHCO3 soln applying standard conditions.
Data of 16: C14H24N205 (300.4). 1H-NMR (DMSO-d6): 7.12 (br. d, J = 6.1, 1 H);
5.91 (m, 1 H); 5.27 (m, 1 H); 5.18 (m, 1 H); 4.49 (m, 2 H); ca 3.9 (br. m, 1 H);
3.89 -3.57 (several m, 4 H); 3.48 (dd, J = 3.1, 10.6, 1 H); 2.95 (br. m, 1 H); 2.21 (br.
m, 1 H);
1.75 (br. m, 1 H); 1.38 (s, 9 H).
tert-Butyl (3R,5S)-5-(hydroxymethyl)pyrrolidin-3-ylcarbamate hydrochloride (17.HCI) is commercially available.
(28,4 R)-Ally1 4-(tert-butoxycarbonylam ino)-2-(hydroxyl methyl)-pyrrolid in-1-carboxy-late (18) was prepared by Alloc protection of the secondary amino group of

17.HCI
with allyl chloroformate in CH2Cl2 in the presence of aq. NaHCO3 soln applying standard conditions.
Data of 18: C14H24N205 (300.4). 1H-NMR (DMSO-d6): 7.08 (br. d, J = 7.1, 1 H);
5.91 (m, 1 H); 5.26 (br. m, 1 H); 5.18 (br. d, J ca 10.4, 1 H); 4.52 (br. m, 2 H), ca 4.1 (br.

m, 2 H); 3.82 (br. m, 1 H); ca 3.5- 3.35 (br. s-like m, 3 H); 3.19 (br. m, 1 H); 2.05 (br.
m, 1 H); 1.79 (br. m, 1 H); 1.38 (s, 9 H).
N-Boc-L-alaninol (19) is commercially available.
N-Boc-D-alaninol (20) is commercially available.
(S)-tert-Butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (21) is commercially available.
(2S ,4S)-Ally14-(4-bromobenzyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (118) was prepared as described in the preceding patent application (WO
2011/014973 A2).
(S)-(+)-Prolinol (119) is commercially available.
(S)-Ally1 2-(hydroxymethyl)pyrrolidine-1-carboxylate (120) was prepared by Alloc protection of the secondary amino group of (S)-(+)-prolinol (119) with ally!
chloroformate in dioxane in the presence of aq. NaHCO3 soln applying standard conditions.
Data of 120: C9H16NO3 (185.2). Fl-MS: 186.1 ([M+Hp-). 1H-NMR (DMSO-d6): 5.92 (m, 1 H); 5.28 (br. dd-like m, 1 H); 5.18 (br. dd-like m, 1 H); 4.72 (br. not resolved m, 1 H);
4.60 - 4.45 (br. not resolved m, 2 H); 3.73 (br. not resolved m, 1 H); 3.50 (br. not resolved m, 1 H); 3.35 - 3.25 (br. not resolved m, 3 H); 2.0 - 1.75 (br. not resolved m, 4H).
(2S,4R)-tert-Butyl 4-amino-2-(hydroxymethyl)pyrrolidine-1-carboxylate hydrochloride (121.HCI) is commercially available.
(2S,4R)-tert-Butyl 4-(benzyloxycarbonylamino)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (122) was prepared by Cbz protection of the primary amino group of 121.HCI with benzyl chloroformate in CH2Cl2 in the presence of aq. Na2003 soln applying standard conditions.
Data of 122: C18H26N205 (350.4). LC-MS (method 1c): Rt = 1.89 (95), 351.3 ([M+H]+).
1H-NM (DMSO-d6): 7.49 (d, J = 6.8, 1 H); 7.42 - 7.28 (m, 5 H); 5.02 (s, 2 H);
4.76 (br. s, 1 H); 4.13 ( br. not resolved m, 1 H), 3.76 (br. not resolved m, 1 H);
3.40 (m, 3 H; partially superimposed by H20 signal); 3.11 (dd; J = 6.4, 10.6, 1 H); 2.07 (br. not resolved m, 1 H); 1.82 (br. not resolved m, 1 H); 1.38 (s, 9 H).
Building blocks for subunits of bridge C (Scheme 7):
(R)-Ally1 4-amino-2-(benzyloxycarbonylamino)butanoate toluene-4-sulfonate (22-pTs0H) was prepared as described for the (S)-enantiomer in the preceding patent application (WO 2011/014973 A2).
(S)-Ally1 2-(benzyloxycarbonylamino)-(5-methylamino)pentanoate hydrochloride (23-HCI) , (S)-5-ally1 1-benzyl 2-(methylamino)pentanedioate hydrochloride (24 HCI) and (S)-5-allyl1-benzyl 2-aminopentanedioate hydrochloride (25 HCI) were prepared as described in the preceding patent application (WO 2011/014973 A2).
Ethyl 2-((2-aminoethyl)(benzyloxycarbonyl)amino)acetate hydrochloride (28-HGI) Ethyl 2-(2-(tert-butoxycarbonylamino)ethylamino)acetate hydrochloride (26.HC1;
25.0 g, 88 mmol) was added to a mixture of dioxane (250 mL) and 1 M aq. Na2CO3 soln (250 mL). After 5 min, CbzCI (17.0 g, 98 mmol) was slowly added and the mixture was stirred for 2 h. Aqueous workup (Et0Ac, sat. aq. NaHCO3; Na2SO4) and FC
(hexane/Et0Ac 8:2 to 1:1) afforded 27 (29.0 g, 85%). A solution of 27 (29.5 g, 77.5 mmol) in 4 M HCI-dioxane (300 mL) was stirred at rt for 2 h and concentrated.
The residue was washed with Et20 to give 28.HCI (24.3 g, 99%).
Data of 28-HCI: C14H20N204-FICI (280.3, free base). LC-MS (method la): Rt =
1.33 (99), 281.1 ([M+H]+). 1H-NMR (DMSO-d6): 8.05 (br. s, NH3); 7.39 - 7.28 (m, 5 arom.
H); 5.12, 5.07(2 s; 2 H); 4.16 - 4.04 (m, 4 H); 3.54 (m, 2 H); 2.97 (br m, 2 H); 1.19, 1.32 (2 t, J = 7.1, 3 H).
(S)-Methyl 2-(tert-butoxycarbonylamino)-6-hydroxyhexanoate (30) At 0 C, iodomethane (8.18 mL, 131 mmol) was added to a suspension of Boc-L-6-hydroxynorleucine (29; 25 g, 101 mmol) and NaHCO3 (42.5 g, 505 mmol) in DMF
(790 mL). The mixture was stirred at 0 C to rt for 16 h. The mixture was filtered. The filtrate was distributed between Et0Ac and 1 M aq. HCI soln. The organic layer was subsequently washed with H20, sat. aq. NaHCO3 soln and sat. aq. NaC1 soln. The organic phase was dried (Na2SO4), filtered, and concentrated to afford 30 (24.54 g, 92%).
Data of 30: C12H23N05 (261.3). Fl-MS: 262.0 ([M+H]-). 1H-NMR (DMSO-d6): 7.21 (d, J
= 7.8, 1 H); 4.36 (t, J = 5.2, 1 H); 3.92 (m, 1 H); 3.61 (s, 3 H); 3.36 (q, J
= 5.8, 2 H);

1.59 (m, 2 H); 1.44 (s, 9 H); 1.44 ¨ 1.26 (m, 4 H).
(S)-3-(((9H-Fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid (31;
Fmoc-33-homoPhe-OH) is commercially available.
3-((((9H-Fluoren-9-yl)methoxy)carbonyl)(methyl)amino)propanoic acid (33; Fmoc-NMe-3-Ala-OH) was prepared from 3-(methylamino)propanoic acid hydrochloride (32.HCI) applying Fmoc-OSu and Na2003 in H20 and dioxane.
Data of 33: C19H19N04 (325.3). LC-MS (method la): R = 1.95 (96), 326.0 ([M+H]).
3-(((9H-Fluoren-9-yl)methoxy)carbonylamino)propanoic acid (34; Fmoc-3-Ala-OH) is commercially available.
Synthesis of (R)-3-((((9H-Fluoren-9-yl)methoxy)carbonyl)(methyDamino)butanoic acid (40; Fmoc-NMe-33-homoDAla-OH) At 0 C, 4 M HCI-dioxane (37.8 mL, 151 mmol) was added dropwise to a mixture of (R)-homo-3-alanine (35; 13.0 g, 126 mmol) in CH2Cl2 (170 mL). PCI5 (31.5 g, mmol) was added to the suspension. The mixture was stirred at 0 C to rt for 15 h. A
clear solution resulted. The volatiles were evaporated. The residue was dissolved in CH2Cl2 (150 mL). Ally! alcohol (10.3 mL, 151 mmol) was added slowly and the mixture was stirred for 2 h at rt. The volatiles were evaporated to afford crude 36.HCI
(25.6 g).
Pyridine (115 mL) was added to a soln of crude 36-HCI (25.5 g) in CH2Cl2 (275 mL).
The mixture was cooled to 0 C, followed by the addition of 4-nitrobenzenesulfonyl chloride (63 g, 284 mmol). The mixture was stirred at 0 C to rt for 16 h. Aq.
workup (CH2Cl2, 1 M aq. HCI soln; Na2SO4) and FC (hexane/Et0Ac 9:1 to 1:1) yielded 37 (26.7 g, 64%).
K2CO3 (56 g, 404 mmol) was added to a solution of 37 (26.5 g, 81 mmol) in DMF
(295 mL). lodomethane (50 mL, 807 mmol) was added at 0 C and the mixture was allowed to warm to rt over 3 h. Aq. workup (Et0Ac, 1 M aq. HCI soln, sat. aq.
NaCI
soln; Na2SO4) gave crude 38 (27.6 g).
K2CO3 (16.7 g, 121 mmol) was added to a soln of crude 38 (13.8 g, ca 40 mmol) in CH3CN (275 mL). The mixture was degassed, cooled to 0 C and treated with thiophenol (6.15 mL , 60 mmol). The mixture was stirred at 0 C to rt for 15 h.

(115 mL) and (in portions) Fmoc-CI (10.5 g, 40.3 mmol) were added. Stirring was continued for 3 h followed by an aq. workup (Et0Ac, sat. aq. Na2CO3; Na2SO4) and FC (hexane/Et0Ac 95:5 to 70:30). The material obtained (11.5 g) was purified again by FC (hexane/CH2Cl2 8:2, then CH2Cl2, then CH2C12/Et0Ac) to give 39 (9.2 g, 60%).
A degassed soln of 39 (18.3 g, 48.2 mmol) in CH2Cl2 (175 mL) / Et0Ac (210 mL) was treated with Pd(PPh3)4 (0.9 g, 0.77 mmol) and 1,3-dimetylbarbituric acid (9.04 g, 57.9 mmol) for 3 h at it. The volatiles were evaporated. FC (CH2C12/Me0H 100:0 to 80:20) afforded 40 (7.55 g, 46%) and impure material which was further purified by prep.
HPLC (method 1d) to give more 40 (5.61 g, 34%).
Data of 40: C201-121N04 (339.4). LC-MS (method 1a): Rt = 2.03 (96), 340.1 ([M+H]).
1H-NMR (DMSO-d6): 12.2 (br. s, 1 H); 7.89 (d, J = 7.4, 2 H); 7.65 (br. s, 2 H); 7.41 (t, J = 7.4, 2 H); 7.33 (t, J = 7.3, 2 H); 4.40 -4.24 (m, 4 H), 2.67 (s, 3 H);
2.45- 2.30 (br.
m, 2 H); 1.37 (br. d, 3 H).
Ally! 2-((2-aminoethyl)(benzyloxycarbonyl)amino)acetate hydrochloride (125.HCI) At 4 C, Li0H.H20 (6.36 g, 152 mmol) was added to a soln of 27 (28.82 g, 75.8 mmol) in Me0H (86 mL), H20 (85 mL) and THF (270 mL). The mixture was stirred for 18 h at it, acidified with 1 M aq. HCI soln (500 mL) and extracted with Et0Ac. The organic phase was dried (Na2SO4), filtered and concentrated to give 123 (26.5 g, 99%).

NaHCO3 (17.7 g, 210 mmol) was added to a soln of 123 (37.1 g, 105.4 mmol) in DMF
(530 mL). The mixture was stirred for 5 min followed by the addn of ally!
bromide (18.0 mL; 208 mmol). The mixture was stirred at it for 18 h. More NaHCO3 (2.0 g, 24 mmol) and ally! bromide (2.0 mL; 23.1 mmol) were added and stirring was continued for 4 h. Aq. Workup (Et0Ac, 1 M aq. HCI soln; Na2SO4) and FC (CH2C12/Me0H
99.5:0.5 to 98:2) afforded 124 (38.8 g, 94%).
A soln of 124 (22.5 g, 53.3 mmol) in dioxane (23 mL) was treated at it with 4 M HCI in dioxane (80 mL) for 3 h. Dioxane (50 mL) was added and stirring was continued for 1 h. The volatiles were evaporated and the residue was washed (Et20) and dried i.v. to yield 125.HCI (17.0 g, 97%).
Data of 125.HCI: C15H20N204-FICI (free base, 292.3). Fl-MS: 292.9 ([M+H]).
IH-NMR (DMSO-d6): 8.03 (br s, 3 H); 7.39 - 7-28 (m, 5 H); 5.87 (m, 1 H); 5.35 -5.17 (m, 2 H); 5.12, 5.07 (2 s, 2 H); 4.59 (m, 2 H); 4.16 (d, J = 7.5, 2 H); 3.54 (q-like m, 2 H); 2.97 (br m, 2 H).
All Fmoc-a-amino acids and Fmoc-N-methyl-a-amino acids applied in the synthesis of Core 10 and Core 11 are commercially available:
Fmoc-L-alanine (Fmoc-Ala-OH) Fmoc-N-methyl-L-alanine (Fmoc-NMe-Ala-OH) Fmoc-D-alanine (Fmoc-DAla-OH) Fmoc-N-methyl-D-alanine (Fmoc-NMe-DAla-OH) Fmoc-N-methyl-L-glutamic acid 5 tert.-butyl ester (Fmoc-NMe-Glu(OtBu)-0H) Fmoc-glycine (Fmoc-Gly-OH) N-a-Fmoc-N-c-Boc-L-lysine (Fmoc-Lys(Boc)-0H) Fmoc-L-phenylalanine (Fmoc-Phe-OH) Fmoc-N-methyl-L-phenylalanine (Fmoc-NMe-Phe-OH) Fmoc-D-phenylalanine (Fmoc-DPhe-OH) Fmoc-N-methyl-D-phenylalanine (Fmoc-NMe-DPhe-OH) Fmoc-sarcosine (Fmoc-Sar-OH) (S)-Methyl 3-(allyloxy)-2-aminopropanoate hydrochloride (129) A soln of Boc-serine (126; 14.0 g, 68.2 mmol) in DMF (143 mL) was cooled to 0 C.
NaHCO3 (17.2 g 205 mmol) was added and the mixture was stirred for 15 min.
lodomethane (8.5 mL, 136 mmol) was added dropwise. The mixture was stirred at 0 C to rt for 16 hand again cooled to 0 C. More iodomethane (4.2 mL, 67 mmol) was slowly added and stirring was continued for 3 h. The mixture was diluted with and extracted with Et0Ac. The organic phase was washed (sat. aq. NaCI soln), dried (Na2SO4), filtered and concentrated to give crude 127 (14.2 g).
A soln of crude 127 (14.2 g) and Pd(PPh3)4 (0.64 g) in THE (416 mL) was degassed.
Carbonic acid allyl methyl ester (9.6 g, 82.8 mmol) was added and the mixture was heated to 60 C for 2 h. The volatiles were evaporated. FC (hexane/Et0Ac 9:1) afforded 128 (11.4 g, 79%) A soln of 128 (11.4 g, 43.9 mmol) in dioxane (110 mL) was treated with 4 M HCI
in dioxane (110 mL) for 4 h at rt. Additional 4 M HCI in dioxane (30 mL) was added and stirring was continued for 30 min. The volatiles were evaporated and the residue was washed with Et20 to give 129.HCI (8.3 g, 96%).
Data of 129 HCI: C7H13NO3HCI (159.2, free base). Fl-MS: 160.0 ([M+Hp-). 1H-NMR

(DMSO-d6): 8.70 (br. s, 3 H); 5.85 (m, 1 H); 5.29 (qd, J = 1.7, 17.3, 1 H), 5.19 (qd, J =
1.5, 10.4, 1 H); 4.33 (t, J = 3.6, 1 H); 4.07 ¨ 3.93 (m, 2 H); 3.86 ¨ 3.78 (m, 2 H); 3.76 (s, 3 H).
(S)-Ally1 2-(benzyloxycarbonylamino)-4-(methylamino)butanoate hydrochloride (130 HCI) and (S)-Ally1 2-(benzyloxycarbonylamino)-6-(methylamino)hexanoate hydrochloride (131 HCI) were prepared described in the preceding patent application (WO
2011/014973 A2).
Sarcosine tert-butylester hydrochloride (132.1-1C1) is commercially available.
Core 01: Synthesis of Ex.1, Ex.2 and Ex.3 (Scheme 8) Synthesis of the Mitsunobu product 41 At 0 C, ADDP (7.08 g, 28.1 mmol) was added in portions to a mixture of phenol (4.27 g, 18.7 mmol), alcohol 16 (6.18 g, 20.6 mmol) and PPh3 (7.36 g, 28.1 mmol) in CHC13 (110 mL). The stirred mixture was allowed to warm to it over 15 h.
The volatiles were evaporated. The residue was suspended in CH2Cl2 and filtered.
The filtrate was concentrated and purified by FC (hexane/Et0Ac 4:1) to yield 41(5.98 g,62%).
Data of 41: C28H34N207 (510.6). LC-MS (method la): Rt = 2.58 (94), 511.2 ([M+H]-).
Synthesis of the acid 42 Aq. LiOH soln (2 M; 11 mL, 22.0 mmol) was added to a solution of ester 41(5.65 g, 11.1 mmol) in Me0H (11 mL) and THF (19 mL). The mixture was heated to 65 C for 4 h, partially concentrated, acidified with 1 M aq. HCI soln to pH 1 and extracted twice with Et0Ac. The combined organic layer was washed (sat. aq. NaCI soln), dried (Na2SO4), filtered and concentrated to give 42 (4.46 g, 81%).
Data of 42: C27H32N207 (496.6). LC-MS (method 1a): Rt = 2.28 (90), 497.2 ([M+H}-).
Synthesis of the amide 43 A solution of acid 42 (4.46 g, 9.0 mmol), amine 22.pTs0H (5.6 g, 11 mmol), HATU
(5.1 g, 13 mmol), HOAt (1.8 g, 13 mmol) in DMF (70 mL) was cooled to 0 C, followed by the addition of i-Pr2NEt (6.2 mL, 36 mmol). The mixture was allowed to warm to it over 15 h. The mixture was diluted with 0.5 M aq. HCI soln and extracted twice with Et0Ac. The combined organic layer was washed (sat. aq. NaCI soln), dried (Na2SO4), filtered and concentrated. FC (hexane/Et0Ac 1:1) of the crude product afforded (5.56 g, 80%).
Data of 43: C42H50N4010 (770.9). LC-MS (method 1a): R = 2.55 (95), 771.3 ([M+Hy).

Synthesis of amino acid 44 A degassed solution of amide 43 (5.55 g, 7.2 mmol) and 1,3-dimethylbarbituric acid (2.5 g, 16 mmol) in CH2Cl2 (40 mL) and Et0Ac (40 mL) was treated with Pd(PPh3)4 (0.41 g, 0.36 mmol) at rt. After 2 h, more CH2Cl2 (40 mL) and Pd(PPh3)4 (0.41 g, 0.36 mmol) were added and stirring was continued for 1 h. The volatiles were evaporated.
The solid was suspended in Et0Ac, filtered, washed (Et0Ac) and dried i.v. to afford 44 (3.94 g, 83%).
Data of 44: C35H42N408 (646.7). LC-MS (method la): Rt = 1.75 (97), 647.2 ([M+1-1]+).
Synthesis of Ex.1 The amino acid 44 (2.77 g, 4.28 mmol) was added in portions over 2 h to a solution of T3P (50% in Et0Ac; 13 mL, 22.1 mmol) and i-Pr2NEt (5.8 mL, 34.3 mmol) in dry CH2Cl2 (800 mL). Stirring was continued for 30 min. The mixture was washed (sat.
aq. NaHCO3 soln.), dried (Na2SO4), filtered and concentrated. FC (CH2Cl2/THF
9:1) of the crude product yielded Ex.1 (2.35 g, 87%).
Data of Ex.1: C35H40N407 (628.7). LC-MS (method la): R = 2.17 (94), 629.2 ([M+H]).
1H-NMR (DMSO-d6): 8.18 (br. t, 1 H); 7.67 (d, J = 7.2, 1 H); 7.52 - 7.23 (m, 11 H);
7.11 -7.06 (m, 2 H); 6.98 (d, J = 8.1, 1 H); 4.98 (s, 2 H); 4.64 (br. m, 1 H);
ca 4.3 -4.0 (several br. m, 4 H); 3.85 (br. m, 1 H); 3.10 (br. m, 1 H); 2.98 (m, 1 H);
2.31 (br.
m, 1 H); ca 2.0 - 1.75 (br. m, 2 H); 1.53 (br. m, 1 H); 1.41 (s, 9 H); 0.83 (br. m, 1 H).
Synthesis of Ex.2 A soln of Ex.1 (300 mg, 0.477 mmol) in Me0H (6.0 mL) was hydrogenated for 16 h at rt and normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50% H20; 63 mg). The mixture was filtered through a pad of celite.
The solid was washed with Me0H. The combined filtrate and washings were concentrated. FC (CH2C12/Me0H 95:5 to 80:20) gave Ex.2 (206 mg, 87%).
Data of Ex.2: C27H34N405 (494.6). LC-MS (method la): Rt= 1.60 (99), 495.2 ([M+H]).
1H-NMR (DMSO-d6): 8.21 (t-like m, 1 H); 7.52 -7.36 (m, 5 H); 7.21 (br. d, 1 H), 7.15 - 7.00 (m, 2 H); 7.00 (s, 1 H), 4.43 (br. not resolved m, 1 H); 4.24 - 4.01 (m, 3 H);
3.89 (q-like m, 1 H); 3.58- 3.12 (several br. m, 3 H); 2.98 (dd, J = 6.2, 12.1, 1 H);
2.33 (m, 1 H); 1.89 (m, 1 H); 1.65 - 1.55 (br. not resolved m, 2 H); 1.41 (s, 9 H).

Synthesis of Ex.3 A soln of Ex.1 (750 mg, 1.19 mmol) in CH2Cl2 (5 mL) was cooled to 0 C. TFA
(2.0 mL) was slowly added and the mixture was stirred at 0 C to rt for 4 h. The volatiles were evaporated. The residue was taken up in CHCI3 and concentrated.
The residue was taken up in CH2Cl2 (6 mL), treated with 4 M HCI in dioxane (2 mL) to give a precipitate. The volatiles were evaporated. The treatment with CH2Cl2/4 M HCI
in dioxane was repeated. The residue was suspended in Et20, filtered, washed (Et20) and dried i.v. to afford Ex.3-1-1C1 (613 mg, 90%).
Data of Ex.3-HCI: C30H32N405HCI (528.6, free base). LC-MS (method la): Rt =
1.55 (99), 529.1 ([M+H]).
Core 01: Synthesis of Ex.330, Ex.331 and the resin 133 (Scheme 8) Synthesis of Ex.330 Sat. aq. NaHCO3 soln (131 mL) and H20 (53.5 mL) were added to a soln of Ex.2 (14.4 g, 29 mmol) in dioxane (131 mL) and THF (78 mL). The mixture was cooled to 0 C. Ally! chloroformate (3.71 mL, 34.9 mmol) was slowly added. Stirring was continued for 2 h at 0 C to rt. The mixture was diluted with sat. aq. Na2CO3 soln and extracted with CH2Cl2. The organic phase was dried (Na2SO4), filtered and concentrated to give Ex.330 (16.18 g, 96%).
Data of Ex.330: C311-138N407 (578.6). LC-MS (method 1c): Rt = 2.06 (97), 578.9 ([M-f-H]).
Synthesis of Ex.331 At 0 C, TFA (40.6 mL) was added to a soln of Ex.330 (15.8 g, 27.3 mmol) in CH2Cl2 (160 mL). The cooling bath was removed and stirring was continued for 2 h. The volatiles were evaporated. The residue was dissolved in CHCI3 (76 mL) and 4 M
HCI
in dioxane (14.0 mL) was added. The volatiles were evaporated. The residue was again taken up in CHCI3 (76 mL), treated with 4 M HCI in dioxane (14.0 mL) and concentrated. The residue was distributed between sat. aq. Na2CO3 soln and Et0Ac.
The organic layer was separated, the aqueous layer repeatedly extracted with Et0Ac.
The combined organic phases were concentrated. The residue was dissolved in CH2Cl2 (200 mL). Then 4 M HCI in dioxane (17.7 mL) was slowly added to give a thick precipitate. The volatiles were evaporated. The residue was suspended in Et20, flitered, washed (Et20) and dried i.v. to afford Ex.331-1-1C1 (12.5 g, 89%).
Data of Ex.331 HCI: C26H30N406.HCI (free base, 478.5). LC-MS (method 1a): Rt =
1.36 (96), 479.2 ([M+H]+). 1H-NMR (DMSO-d6): 8.43 (br. s, 3 H); 8.27 (br. t, J
ca 5.3, 1 H); 7.67 (d, J = 6.9, 1 H); 7.52 - 7.37 (m, 5 H); 7.12 - 7.09 (m, 2 H); 7.02 (d, J =
8.8, 1 H); 5.88 (m, 1 H); 5.26 (dd, J = 1.2, 17.2, 1 H); 5.17 (dd, J = 1,1, 10.4, 1 H);
4.67 (br. m, not resolved, 1 H); 4.43 (d, J = 5.2, 2 H); 4.31 - 4.11 (m, 4 H);
3.56 (br.
m, not resolved, 1 H); 3.31 -3.16 (br. m, 2 H); 3.19 (dd, J = 8.1, 12.1, 1 H);
2.60 (m, 1 H); 2.12 (m, 1 H); 1.83 (br. m, 1 H); 1,.47 (br. m, 1 H).
Synthesis of the resin 133 Under Ar, DFPE polystyrene (1% DVB, 100 - 200 mesh, loading 0.87 mmol/g; 11.1 g, 9.6 mmol) was swollen in DOE (110 mL) for 1 h. Ex.331.HCI (5.7 g, 10. 6 mmol) and i-Pr2NEt (4.9 mL, 28.9 mmol) were added. The mixture was shaken at rt for 1 h.
NaBH(OAc)3 (4.09 g, 19.3 mmol) was added and the mixture was shaken for 20 h.
The resin was filtered and successively washed with Me0H twice, then three times each with DOE, 10% i-Pr2NEt in DMF, DMF, CH2Cl2 and Me0H. The resin was dried i.v. to give 133 (15.73 g; loading 0.6 mmol/g).
Procedure D:
Core 01: Synthesis of final products on solid support Synthesis of resin 134 1) First derivatization step Resin 133 (loading 0.6 mmol/g; 96 mg, 0.055 mmol) was swollen in DMF (1 mL) for 60 min and filtered. The resin was resuspended in DMF/0H20I2 1:1 (1 mL). i-Pr2NEt (8 equiv.) the carboxylic acid R"CO2H (4 equiv.) and HATU (4 equiv.) or the succinimidyl carbamate R"NHCO2Su (4 equiv.) were added. The mixture was shaken for 1 h and filtered. The resin was washed with DMF. The coupling step was repeated. The resin was washed three times with DMF.
2) Cleavage of the Alloc group The resin was suspended in CH2Cl2 (1 mL). Phenylsilane (10 equiv.) and Pd(PPh3)4 (0.2 equiv.) were added, then the mixture was shaken for 15 min and filtered.
The deprotection step was repeated. The resin was filtered, washed three times each with CH2Cl2, DMF, twice with Me0H and three times with CH2Cl2.
3) Second derivatization step The resin was resuspended in DMF/CH2Cl2 1:1 (1 mL). i-Pr2NEt (8 equiv.) and the carboxylic acid RIvCO2H (4 equiv.) and PyBOP (4 equiv.) or the isocyanate RIvNCO
(4 equiv) or the sulfonyl chlorides RIvS02C1 (4 equiv) and DMAP (1 equiv.) were added. The mixture was shaken for 1 h and filtered. The resin was filtered, washed three times with DMF to afford resin 134.
Release of the final products The resin 134 was treated with 20% TFA in CH2Cl2 (1 mL) for 30 min, filtered and washed with CH2Cl2. The cleavage step was repeated once. The combined filtrates and washings were concentrated. The residue was treated with CH3CN, evaporated and dried i.v. Purification of the crude product by normal phase or reverse phase prep. HPLC afforded Ex. 7 and Ex.332 - Ex.337.
Core 01: Synthesis of selected advanced intermediates and final products (Scheme 8) Synthesis on solid support:
Ex.7 CF3CO2H (6.6 mg, 15%) was obtained by treatment of resin 133 (0.6 mmol/g, mg, 0.055 mmol) with 1-pyrrolidineacetic acid (in total 57 mg, 0.44 mmol;
first coupling step) and with 1-naphthaleneacetic acid (41 mg, 0.22 mmol, second coupling step) according to procedure D. The product was purified by prep.
HPLC
(method 1a).
Data of Ex.7-CF3CO2H: cf. Table 13b.
1H-NMR (DMSO-d6): 9.94 (br. s, 1 H); 8.77 (d, J = 5.3, 1 H); 8.65 (d, J = 7.7, 1 H);
8.06 (t, J = 5.4, 1 H); 8.01 (m, 1 H); 7.92 (m, 1 H); 7.81 (d, J = 7.9, 1 H);
7.55 - 7.37 (m, 8 H); 7.34 (t, J = 8.0, 1 H); 7.09 - 7.05 (m, 2 H); 6.91 (dd, J = 2.0, 8.2, 1 H); 4.58 (br. not resolved m, 1 H); 4.44 (br. not resolved m, 1 H); 4.19 (dd, J = 4.9, 11.5, 1 H);
4.12 -4.00 (m, 5 H); 3.94 (d, J= 14.9, 1 H); 3.87 (d, J = 14.9, 1 H); ca 3.6 -3.5 (br m, 2 H), 3.30 (1 H, superimposed by H20 signal); 3.07 -3.02 (br. m, 4 H); 2.15 -1.84 (br. m, 7 H); 1.67 (br. m, 1 H).
Ex.332 CF3CO2H (21 mg, 48%) was obtained by treatment of resin 133 (0.6 mmol/g, 96 mg, 0.055 mmol) with imidazol-1-y1 acetic acid (in total 55 mg, 0.44 mmol;
first coupling step) and with 1-naphthaleneacetic acid (41 mg, 0.22 mmol, second coupling step) according to procedure D. The product was purified by prep.
HPLC
(method la).
Data of Ex.332-CF3CO2H: cf. Table 13b.
Ex.333.CF3CO2H (29 mg, 65%) was obtained by treatment of resin 133 (0.6 mmol/g, 96 mg, 0.055 mmol) with 2,5-dioxopyrrolidin-1-y1 pyridine-3-ylcarbamate (in total 103 mg, 0.44 mmol; first coupling step) and with 1-naphthaleneacetic acid (41 mg, 0.22 mmol, second coupling step) according to procedure D. The product was purified by prep. HPLC (method 1a).
Data of Ex.333-CF3CO2H: cf. Table 13b.
Ex.334.CF3CO2H (16 mg, 38%) was obtained by treatment of resin 133 (0.6 mmol/g, 96 mg, 0.055 mmol) with 1-pyrrolidineacetic acid (in total 57 mg, 0.44 mmol;
first coupling step) and with 3-chlorophenylacetic acid (37 mg, 0.22 mmol, second coupling step) according to procedure D. The product was purified by prep.
HPLC
(method la).
Data of Ex.334-CF3CO2H: cf. Table 13b.
Ex.335 CF3CO2H (11 mg, 26%) was obtained by treatment of resin 133 (0.6 mmol/g, 96 mg, 0.055 mmol) with 1-pyrrolidineacetic acid (in total 57 mg, 0.44 mmol;
first coupling step) and with cyclohexylacetic acid (31 mg, 0.22 mmol, second coupling step) according to procedure D. The product was purified by prep. HPLC (method 1a).
Data of Ex.335 CF3CO2H: cf. Table 13b.
Ex.336.CF3CO2H (6 mg, 13%) was obtained by treatment of resin 133 (0.6 mmol/g, 96 mg, 0.055 mmol) with 1-pyrrolidineacetic acid (in total 57 mg, 0.44 mmol;
first coupling step) and with 1-naphthyl isocyanate (0.031 mL, 0.22 mmol, second coupling step) according to procedure D. The product was purified by prep.
HPLC
(method 1a).
Data of Ex.336CF3CO2H: cf. Table 13b.
IH-NMR (DMSO-d6): 9.94 (br. s, 1 H); 8.81 (d, J = 4.9, 1 H); 8.63 (s, 1 H);
8.27 (t, J =
5.6, 1 H); 8.06 (d, J = 8.0, 1 H); 7.96 (dd, J = 1.0, 7.6, 1 H); 7.89 (d, J ca 9.3, 1 H);
7.59 - 7.38 (m, 9 H); 7.16 - 7.13 (m, 2 H); 7.04 - 6.99 (t-like m, 2 H); 4.82 (br. not resolved m, 1 H); 4.45 (t-like m, 1 H); 4.29 (dd, J = 5.9, 11.5, 1 H); 4.22 -4.13 (br. m, 3 H); 4.01 (s, 2 H); 3.65 - 3.45 (br. m, 3 H); 3.25 - 3.0 (br. m, 4 H); 2.45 (m, 1 H);
2.10 - 1.70 (br. m, 7 H).
Synthesis in solution:
Synthesis of Ex.4 At rt, i-Pr2NEt (0.27 mL, 1.57 mmol) was added to a soln of Ex.2 (258 mg, 0.52 mmol), 1-naphthaleneacetic acid (117 mg, 0.63 mmol), HATU (298 mg, 0.78 mmol) and HOAt (107 mg, 0.78 mmol) in DMF (4.3 mL). The mixture was stirred at rt for 15 h and distributed between CH2Cl2 and 1 M aq. Na2CO3 soln. The organic phase was separated, washed (H20), dried (Na2SO4), filtered and concentrated. FC
(hexane/Et0Ac 34:66 to 0:100) afforded Ex.4 (267 mg, 77%).
Data of Ex.4: cf. Table 13b Synthesis of Ex.5 A soln of Ex.4 (220 mg, 0.33 mmol) in dioxane (4.0 mL) was treated with 4 M
HCI-dioxane (1.0 mL) for 2h. The volatiles were evaporated to afford Ex.5.HCI (208 mg, quant.) Data of Ex.5-FICI: cf. Table 13b Synthesis of Ex.7 At rt, i-Pr2NEt (0.057 mL, 0.33 mmol) was added to a soln of Ex.5 HCI (50 mg, 0.08 mmol), 1-Pyrrolidineacetic acid (22 mg, 0.17 mmol), HATU (63 mg, 0.17 mmol) and HOAt (23 mg, 0.17 mmol) in DMF (1.2 mL). The mixture was stirred at it for 4 h and distributed between Et0Ac and sat. aq. NaHCO3 soln. The organic phase was dried (Na2SO4), filtered and concentrated. FC (CH2C12/Me0H 100:0 to 95:5) afforded Ex.7 (40 mg, 71%).
Data of Ex.7: C40F143N505 (673.8). LC-MS (method la): Rt = 1.70 (96), 674.2 ([M+H]).
Synthesis of Ex.14 At 0 C, phenyl chloroformate (87 mg, 0.55 mmol) was slowly added to a mixture of Ex.3 (285 mg, 0.50 mmol) in CH2Cl2 (5 mL) and sat. aq. Na2CO3 soln (1.7 mL).
Stirring was continued for 2 h. Aqueous workup (Et0Ac, sat. aq. NaHCO3 soln., Na2SO4) and FC (Et0Ac) afforded Ex.14 (315 mg, 96%) Data of Ex.14: cf. Table 13b Core 02: Synthesis of Ex.15, Ex.16 and Ex.17 (Scheme 9) Synthesis of the Mitsunobu product 45 At 0 C, a solution of TMAD (7.57 g, 43.9 mmol) in benzene (80 mL) was added dropwise to a degassed solution of the phenol 4 (3.68 g, 16.1 mmol), alcohol 16 (4.40 g, 14.65 mmol) and PPh3 (11.5 g, 43.9 mmol) in benzene (80 mL). The stirred mixture was allowed to warm to it over 15 h.

The volatiles were evaporated. The residue was suspended in hexane and filtered.
The filtrate was concentrated and purified by FC (hexane/Et0Ac 5:1) to yield 45 (5.45 g, 73%).
Data of 45: C28H34N207 (510.6). LC-MS (method 1c): Rt = 2.67 (97), 511.2 (1M+H]+).
Synthesis of the acid 46 At 0 C, aq. LiOH soln (2 M; 10.6 mL, 21.1 mmol) was added to a solution of ester 45 (5.4 g, 10.6 mmol) in Me0H (10 mL) and THF (20 mL). The mixture was allowed to warm to rt over 16 h. The volatiles were evaporated. The residue was taken up in 1 M
aq. HCI soln and extracted twice with Et0Ac. The combined organic layer was dried (Na2SO4), filtered and concentrated. FC (hexane/Et0Ac 2:1 to 0:100 then Et0Ac/Me0H 100:0 to 90:10 gave 46 (4.48 g, 85%).
Data of 46: C27H32N207 (496.6). LC-MS (method 1c): Rt = 2.29 (99), 497.2 ([M+1-1]+).
Synthesis of the amide 47 A solution of acid 46 (4.28 g, 8.6 mmol), amine 23.HCI (4.6 g, 10.3 mmol), HATU (4.9 g, 12.9 mmol) and HOAt (1.76 g, 12.9 mmol) in DMF (80 mL) was cooled to 0 C, followed by the addition of i-Pr2NEt (5.9 mL, 34.5 mmol). The mixture was allowed to warm to rt over 15 h. The mixture was diluted with H20 and Et0Ac. The organic layer was washed (aq. 1 M HC1 soln, sat. aq. NaCI soln), dried (Na2SO4), filtered and concentrated. FC (hexane/Et0Ac 1:1) of the crude product afforded 47 (6.1 9,89%).
Data of 47: C44H54N4010 (798.9). LC-MS (method la): Rt = 2.72 (97), 799.4 ([M+H]).
Synthesis of amino acid 48 A degassed solution of 47 (6.14 g, 7.7 mmol) and 1,3-dimethylbarbituric acid (2.64 g, 16.9 mmol) in CH2Cl2 (70 mL) and Et0Ac (42 mL) was treated with Pd(PPh3)4 (0.44 g, 0.38 mmol) at rt for 1 h. The volatiles were evaporated. FC (Et0Ac, then CH2C12/Me0H 98:2 to 80:20) afforded 48 (4.64 g, 89%).
Data of 48: C37H46N408 (674,8). LC-MS (method la): Rt = 1.86 (97), 675.3 ([M+Hr-).
Synthesis of Ex.15 A soln of the amino acid 48 (1.12 g, 1.66 mmol) in CH2Cl2 (60 mL) was added dropwise over 2 h by syringe pump to a soln of T3P (50% in Et0Ac; 2.45 mL, 4.15 mmol) and i-Pr2NEt (1.14 mL, 6.64 mmol) in dry CH2Cl2 (770 mL). Evaporation of the volatiles, aq. workup (Et0Ac, sat. aq. NaHCO3 soln; Na2SO4) and FC
(hexane/Et0Ac 50:50 to 0:100) yielded Ex.15 (0.96 g, 88%).

Data of Ex.15: C37H44N407 (656.7). LC-MS (method 1d): Rt = 2.29 (97), 657.3 ([M+Hr). 1H-NMR (DMSO-d6): 7.6 -7.0 (br. m, 13 H); 7.13 (d, J = 7.9, 1 H);
7.03 (t, J
= 7.3, 1 H); 5.01 (br. s, 2 H); 4.37 (br. d, J ca 9.7, 1 H); ca 4.25 -3.7 (several br. m, 4 H); 3.25 (br. m, 1 H); 2.95 (br. s, 3 H); 2.64 (br. m, 1 H); 2.40 (br. m, 1 H); 2.18 (br. m, 1 H); ca. 1.85- 1.0 (several br. m, 6 H); 1.37 (s, 9 H).
Synthesis of Ex.16 A soln of Ex.15 (1.3 g, 2.0 mmol) in Me0H (60 mL) was hydrogenated for 4 h at it and normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50% H20; 240 mg). The mixture was filtered through a pad of celite and Na2SO4. The solid was washed with Me0H. The combined filtrate and washings were concentrated to give Ex.16 (1.03 g, 99%).
Data of Ex.16: C29H38N405 (522.6). LC-MS (method la): Rt = 1.68 (97), 523.1 ([M+ H]).
Synthesis of Ex.17 A soln of Ex.15 (600 mg, 0.91 mmol) in dioxane (6 mL) was treated with 4 M HCI
in dioxane (6 mL) at rt for 1 h followed by evaporation of the volatiles. The residue was taken up in CHCI3 and concentrated to afford Ex.17 (571 mg, quant. yield).
Data of Ex.17=HCI: C32H36N406-HCI (556.6, free base). LC-MS (method la): Rt =
1.65 (96), 557.2 ([1\A+Hr-).
Core 02: Synthesis of selected advanced intermediates and final products (Scheme 9) Synthesis of Ex.18 At 0 C, i-Pr2NEt (0.635 mL, 3.71 mmol) was added dropwise to a soln of Ex.17-HCI
(550 mg, 0.93 mmol), 2-naphthaleneacetic acid (207 mg, 1.11 mmol), HATU (529 mg, 1.39 mmol) and HOAt (189 mg, 1.39 mmol) in DMF (10 mL). The mixture was stirred at 0 C for 4 h and distributed between Et0Ac and 0.2 M aq. HCI soln.
The organic phase was separated, washed (H20, sat. aq. NaCI soln), dried (Na2SO4), filtered and concentrated. FC (Et0Ac) afforded Ex.18 (530 mg, 79%).
Data of Ex.18: cf. Table 14b Synthesis of Ex.19 A soln of Ex.18 (520 mg, 0.72 mmol) in Me0H (5 mL) was hydrogenated for 4 h at it and normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50% H20; 94 mg). The mixture was filtered through a pad of celite.
The solid was washed with Me0H. The combined filtrate and washings were concentrated to give Ex.19 (412 mg, 97%).
Data of Ex.19: cf. Table 14b Synthesis of Ex.20 i-Pr2NEt (0.043 mL, 0.25 mmol) was added to a soln of Ex.19 (50 mg, 0.085 mmol), 2-(dimethylamino)acetic acid (17 mg, 0.17 mmol), HATU (64 mg, 0.17 mmol) and HOAt (23 mg, 0.17 mmol). The mixture was stirred at rt for 15 h and distributed between CH2Cl2 and sat. aq. Na2CO3soln. The organic phase was separted, dried (Na2SO4), filtered and concentrated. FC (CH2C12/Me0H 95:5 to 90:10) afforded Ex.20 (17 mg, 30%).
Data of Ex.20: cf. Table 14b Synthesis of Ex.25 Phenylacetyl chloride (0.013 mL, 0.098 mmol) was added at 0 C to a soln of Ex.19 (50 mg, 0.085 mmol) and pyridine (0.034 mL, 0.42 mmol) in CH2Cl2 (0.5 mL). The mixture was stirred at 0 C for 2 h followed by the addition of more phenylacetyl chloride (0.006 mL, 0.045 mmol). Stirring was continued for 1 h. Evaporation of the volatiles and prep. HPLC (method la) afforded Ex.25 (36 mg, 60%).
Data of Ex.25: cf. Table 14b Synthesis of Ex.26 Benzoyl chloride (0.012 mL, 0.10 mmol) was added at 0 C to a soln of Ex.19 (50 mg, 0.085 mmol) and pyridine (0.034 mL, 0.42 mmol) in CH2Cl2 (0.5 mL). The mixture was stirred at 0 C for 2 h followed by evaporation of the volatiles and prep.
HPLC
(method la) to afford Ex.26 (40 mg, 67%).
Data of Ex.26: cf. Table 14b Core 03: Synthesis of Ex.41, Ex.42, Ex.50 and Ex.62 - Ex.67 (Scheme 10) Synthesis of the Mitsunobu product 49 At 0 C, ADDP (7.32 g, 29.0 mmol) was added in portions to a mixture of phenol (5.0 g, 19.4 mmol), alcohol 20 (5.08 g, 29.0 mmol) and PPh3 (7.62 g, 29.0 mmol) in CHCI3 (82 mL). The stirred mixture was allowed to warm to rt over 15 h.

More 20 (5.08 g, 29.0 mmol), PPh3 (7.62 g, 29.0 mmol) and finally ADDP (7.32 g, 29.0 mmol) were added at 0 C. Stirring was continued at rt for 6 h. The mixture was filtered. The filtrate was concentrated and purified by FC (hexane/Et0Ac 90:10 to 80:20) to yield 49 (7.57 g, 94%).
Data of 49: C23H29N06 (415.5). LC-MS (method 1a): R = 2.54 (99), 416.2 ([1\n+El]+).
Synthesis of the acid 50 At 0 C, aq. LiOH soln (2 M; 27 mL, 54.0 mmol) was added dropwise to a solution of ester 49 (7.44 g, 17.9 mmol) in Me0H (27 mL) and THF (50 mL). The mixture was stirred at rt for 5 h, partially concentrated, acidified with 1 M aq. HCI soln and extracted twice with Et0Ac. The combined organic layer was dried (Na2SO4), filtered and concentrated to give 50 (7.1 g, 98%).
Data of 50: C22H27N06 (401.4). LC-MS (method la): Rt = 2.20 (98), 402.1 ([M+H]).
Synthesis of the amide 51 A solution of acid 50 (7.0 g, 17.4 mmol), amine 24.HCI (6.86 g, 20.9 mmol), HATU
(9.95 g, 26.2 mmol) and HOAt (3.56 g, 26.2 mmol) in DMF (180 mL) was cooled to 0 C, followed by the addition of i-Pr2NEt (11.9 mL, 69.7 mmol). The mixture was allowed to warm to rt over 7 h. More 24 HCI (6.86 g, 20.9 mmol) was added and stirring continued for 15 h. The mixture was diluted with 1 M aq. HCI soln and extracted twice with Et0Ac. The combined organic layer was washed (H20, sat.
aq.
NaCl soln), dried (Na2SO4), filtered and concentrated. FC (hexane/Et0Ac 2:1) of the crude product afforded 51 (10.05 g, 85%).
Data of 51: C38H46N209 (674.8). LC-MS (method 1a): R = 2.69 (97), 675.2 ([M+H]).
Synthesis of the amino ester 52 A soln of 51 (10.0 g, 14.8 mmol) in dioxane (10 mL) was treated at rt with 4 M
HCI in dioxane (40 mL) for 5 h. The volatiles were evaporated. The residue was taken up in CH2Cl2 and concentrated to afford 52 HCI (9.2 g, quant. yield).
Data of 52.HCI: C33H38N2O7HCI (574.6, free base). LC-MS (method la): R = 1.94 (94), 575.2 ([M-FH]+).
Synthesis of amino acid 53 A degassed solution of ester 52 (9.2 g, 15 mmol) and 1,3-dimethylbarbituric acid (2.8 g, 18 mmol) in CH2Cl2 (30 mL) and Et0Ac (60 mL) was treated with Pd(PPh3)4 (1.8 g, 1.5 mmol) at it for 2 h. The volatiles were evaporated. FC (CH2C12/Me0H 98:2 to 70:30) afforded 53 (8.2 g, quant.).
Data of 53: C30H34N207 (534.6). LC-MS (method 1a): R = 1.70 (94), 535.2 ([M+H]).
Synthesis of Ex.41 A soln of the amino acid 53 (4.0 g, 7.5 mmol) in CH2Cl2 (80 mL) was added dropwise over 2 h by syringe pump to a soln of T3P (50% in Et0Ac; 11.0 mL, 18.7 mmol) and i-Pr2NEt (5.12 mL, 29.9 mmol) in dry CH2Cl2 (1360 mL). Evaporation of the vol atiles, aq. workup (CH2Cl2, sat. aq. NaHCO3 soln; Na2SO4) and FC (hexane/Et0Ac 20:80 to 0:100) yielded Ex.41 (3.0 g, 77%).
Data of Ex.41: C30H32N206 (516.5). LC-MS (method 1d): R = 2.14 (96), 517.0 ([M+1-1]+). 1H-NMR (CDCI3): 7.78 (s, 1 H); 7.50 - 7.35 (m, 7 H); 7.25 (m, 1 H), 6.92 -6.82 (m, 3 H); 5.59 (d, J = 8.4, 1 H); 5.32 (d, J = 12.2, 1 H); 5.26 (d, J =
12.2, 1 H);
4.78 (d, J = 11.9,1 H); 4.16 (q-like m, 1 H); 3.81 (s, 3 H); 3.71 (d, J = 9.0, 1 H); 3.38 (Nike m, 1 H); 2.98 (s, 3 H); 2.64 (br. t, J ca. 12.7, 1 H); 2.37 (dd, J =
5.6, 16.2, 1 H);
2.01 - 1.90 (m, 2 H); 1.24 (d, J = 6.8, 3 H).
Synthesis of Ex.42 A soln of Ex.41 (2.0 g, 3.87 mmol) in Me0H (30 mL) was hydrogenated for 2 h at it and normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50% H20; 220 mg). The mixture was filtered through a pad of celite.
The solid was washed with Me0H. The combined filtrate and washings were concentrated to give Ex.42 (1.77 g, quant. yield).
Data of Ex.42: C23H26N206 (426.5). LC-MS (method 1d): R = 1.55 (93), 427.0 ([M+H]). 1H-NMR (DMSO-d6): 13.2 (br. s, 1 H); 8.03 (d, J = 8.2, 1 H); 7.59 (s, 1 H);
7.46 - 7.41 (m, 2 H); 7.16 (m, 1 H); 7.04 (d, J = 8.9, 1 H); 6.90 (dd, J =
3.0, 8.8, 1 H);
6.83 (d, J = 3.0, 1 H); 4.13 (dd, J = 3.0, 12.2, 1 H); 4.03 - 3.91 (m, 2 H);
3.74 (s, 3 H);
3.52 (t, J = 9.2, 1 H); 2.86 (s, 3 H); 2.39 (br. t, J ca 13.2, 1 H); 2.19 (br.
dd, J ca 4.9, 15.9, 1 H); 1.99 (d-like m, 1 H); 1.86 (m, 1 H); 1.03 (d, J = 6.6,3 H).
Core 03: Synthesis of selected advanced intermediates and final products (Scheme 10) Synthesis of Ex.62 A soln of Ex.41 (50 mg, 0.1 mmol) in THF (1 mL) was cooled to 0 C. L1BH4 (5 mg, 0.213 mmol) and Me0H (3.9 pL, 0.1 mmol) in THF (0.5 mL) were added. The mixture was stirred at rt for 20 h followed by the addition of acetone (0.1 mL).
Aqueous workup (CHCI3, 1 M aq. HCI soln, H20, sat. aq. NaHCO3 soln, sat. aq. NaCI
soln;
Na2SO4) and FC (CH2C12/Me0H 100:0 to 90:10) yielded Ex.62 (25 mg, 61%).
Data of Ex.62: C23H28N205 (412.5). LC-MS (method la): Rt = 1.49 (97), 413.0 ([M+H]-). 1H-NMR (DMSO-d6): 7.90 (d, J = 8.2, 1 H); 7.56 - 7.53 (m, 2 H); 7.41 - 7.32 (m, 2 H); 7.00 (d, J = 8.9, 1 H); 6.89 (dd, J = 3.1, 8.9, 1 H); 6.80 (d, J =
3.1, 1 H); 5.05 (t, J = 5.3, 1 H); 4.01 -3.87 (m, 2 H); 3.74 (s, 3 H); 3.74 (m, 1 H); 3.61 -3.38 (m, 3 H); 2.78 (s, 3 H); 2.11 (dd, J = 5.6, 15.9, 1 H); 1.99 (br.t, 1 H); 1.85 (br.t, 1 H); 1.45 (dt, J = 6.1, 12.7, 1 H); 1.00 (d, J = 6.7, 3 H).
Synthesis of Ex.63 At 0 C, DEAD (40% in toluene; 0.05 mL, 0.109 mmol) was slowly added to a soln of Ex.62 (30 mg, 0.073 mmol), 3-hydroxypyridine (8.3 mg, 0.087 mmol) and PPh3 (29 mg, 0.109 mmol) in degassed benzene/THF 1:1 (2 mL) . The mixture was stirred at rt for 16 h and concentrated. FC (CH2C12/Me0H 100:0 to 90:10) afforded Ex.63 (26 mg, 73%).
Data of Ex.63: C28H31N305 (489.5). LC-MS (method la): Rt = 1.44 (95), 490.1 Synthesis of Ex.64 At 0 C, DEAD (40% in toluene; 0.83 mL, 1.82 mmol) was slowly added to a soln of Ex.62 (250 mg, 0.61 mmol), PPh3 (477 mg, 1.82 mmol) and DPPA (0.394 mL; 1.82 mmol) in degassed benzene (10 mL) . The mixture was stirred for 30 min at rt and for 1 h at 50 C. The volatiles were evaporated. The residue was suspended in Et20.
The solid was collected to afford Ex.64 (169 mg, 63%).
Data of Ex.64: C23H27N504 (437.5). LC-MS (method la): R = 1.86 (94), 438.2 Synthesis of Ex.65 A soln of Ex.64 (166 mg, 0.38 mmol) in Me0H/CH2C12 2:1 (3 mL) was hydrogenated at rt for 4 h in the presence of palladium hydroxide on activated charcoal (moistened with 50% H20; 71 mg). The mixture was filtered through a pad of celite. The solid was washed with Me0H. The combined filtrate and washings were concentrated. The residue was dissolved in CHCI3 and evaporated. The residue was dissolved in CH2Cl2 (3 mL), treated with 4 M HCI-dioxane (0.285 mL, 1.1 mmol). A precipitate was obtained which was filtered and washed (Et0Ac) to afford Ex.65 HC1 (149 mg, 87%).

Data of Ex.65-HCI: C23H29N304 (411.5). LC-MS (method 1a): R = 1.35 (86), 412.2 ([M+ H]).
Synthesis of Ex.66 At 0 C, i-Pr2NEt (0.076 mL, 0.45 mmol) was added dropwise to a soln of Ex.65.HCI
(50 mg, 0.11 mmol), phenylacetic acid (18 mg, 0.13 mmol), HATU (64 mg, 0.17 mmol) and HOAt (23 mg, 0.167 mmol) in DMF (0.5 mL). The mixture was stirred at 0 C for 2 h. Aq. workup (Et0Ac, 0.2 M HCI soln, H20, sat. aq. NaCI soln;
Na2SO4) and prep. HPLC (method 3) afforded Ex.66 (33 mg, 55%).
Data of Ex.66: C31H35N305 (529.6). LC-MS (method 1a): R1 = 1.89 (91), 530.2 ([M+ H]).
Synthesis of Ex.67 i-Pr2NEt (0.031 mL, 0.18 mmol) was added to a soln of Ex.62 (50 mg, 0.12 mmol) and phenyl isocyanate (17 mg, 0.15 mmol) in THF / DMF 1:1 (1.0 mL). The mixture was stirred at rt for 16 h followed by an aq. workup (CHCI3, sat. aq. Na2CO3 soln;
Na2SO4) and prep. HPLC (method 3) to afford Ex.67 (46 mg, 72%).
Data of Ex.67: C30H33N306 (531.6). LC-MS (method 1a): Rt = 2.06 (90), 532.2 ([M+Fi]+).
Synthesis of Ex.50 3-Picolylamine (0.014 mL, 0.141 mmol) and i-Pr2NEt (0.06 mL, 0.352 mmol) were slowly added to a cold solution of Ex.42 (50 mg, 0.117 mmol), HATU (67 mg, 0.176 mmol) and HOAt (24 mg, 0.176 mmol) in DMF (0.5 mL). The mixture was stirred for 2 h at 4 C, followed by an aqueous workup (CH2Cl2, 1 M aq. HCI soln, sat. aq.
NaCI
soln; Na2SO4) and purification by prep HPLC (method 1c) to give Ex.50 CF3CO2H
(28 mg, 37%).
Data of Ex.50-CF3CO2H: cf. Table 15b.
1H-NMR (DMSO-d6 and D20): 8.90 (br. s, 1 H); 8.50 (very br. s, 1 H); 7.56 (s, 1 H);
7.40 (br. s, 1 H); 7.30 (very br. s, 1 H); 7.01 (m, 2 H); 6.88 (dd, J = 2.9, 8.9, 1 H); 6.78 (d, J = 2.7, 1 H); 4.60 (br. not resolved m, 2 H); 4.08 (br. d, J = 9.8, 1 H);
3.98 - 3.89 (br. m, 2 H); 3.71 (s, 3 H); 3.51 (t, J = 9.2, 1 H); 2.84 (s, 3 H); 2.43 (br.
not resloved m, 1 H), 2.21 (br. m, 1 H); 1.96 - 1.76 (m, 2 H); 1.00 (d, J = 6.5,3 H).
An analytical sample of Ex.50.CF3CO2H was dissolved in CH2Cl2 and washed with sat. aq. Na2CO3 soln. The organic phase was separated, dried (Na2SO4) and concentrated to give Ex.50.

Data of Ex.50: 1H-NMR (DMSO-c16): 8.88 (t, J = 6.0, 1 H); 8.59 (d, J = 1.6, 1 H); 8.56 (dd, J = 1.5, 4.8, 1 H); 8.09 (d, J = 8.2, 1 H); 7.82 (td, J = 1.9, 7.9, 1 H);
7.67 (s, 1 H);
7.50 -7.44 (m, 2 H); 7.32 (t, J = 7.6, 1 H); 7.13 -7.08 (m, 2 H); 6.95 (dd; J
= 3.1, 8.9, 1 H); 6.87 (d, J = 3.1, 1 H); 4.43 - 4.40 (m, 2 H); 4.15 - 3.96 (m, 3 H); 3.80 (s, 3 H);
3.57 (t, J ca 9.0, 1 H); 2.91 (s, 3 H); ca 2.5 (1 H, superimposed by DMSO-d signal);
2.26 (br. dd, 1 H); 1.98 (br. dd, 1 H), 1.81 (dt; J = 5.3, 10.0, 1 H); 1.08 (d, J = 6.7, 3 H).
Core 04: Synthesis of Ex.68 and Ex.69 (Scheme 11) Synthesis of the Mitsunobu product 54 ADDP (6.61 g, 26.2 mmol) was added to a mixture of the phenol 8 (3.98 g, 17.5 mmol), the alcohol 19 (4.59 g, 26.2 mmol) and PPh3 (6.87 g, 26.2 mmol) in (160 mL). The mixture was stirred at rt for 15 h. Silica gel (20 g) was added.
The volatiles were evaporated and the residue was purified by FC (hexane/Et0Ac 5:1) to give 54 (3.2 g, 48%).
Data of 54: C22H27N05 (385.5). LC-MS (method 2b): Rt = 2.56 (90), 384.0 ([1V1-1-I]).
Synthesis of the acid 55 LiOH=H20 (1.6 g, 38 mmol) was added to a solution of ester 54 (4.89 g, 12.7 mmol) in THF (72 mL), Me0H (24 mL) and H20 (24 mL). The mixture was stirred at rt for 4.5 h, partially concentrated, diluted with H20 (30 mL), acidified with 1 M aq. HCI
soln (ca 40 mL) and extracted twice with Et0Ac. The combined organic layer was dried (Na2SO4), filtered and concentrated to give 55 (4.67 g, 99%).
Data of 55: C21H25N05 (371.4). LC-MS (method 2a): Rt = 1.32 (98), 369.9 ([M-H]-).
Synthesis of the amide 56 PyClu (2.2 g, 6.62 mmol) and i-Pr2NEt (2.95 mL, 17.3 mmol) were successively added to a solution of acid 55 (2.14 g, 5.76 mmol) and amine 24 HCI (2.52 g, 7.7 mmol), in DMF (50 mL). The mixture was stirred at rt for 1 h followed by an aq.
workup (Et20, 0.5 M aq. HCI soln, H20, sat. aq. NaCI soln; Na2SO4). FC
(hexane/Et0Ac 7:3 to 4:6) afforded 56 (2.29 g, 61%).
Data of 56: C37F14.4N208 (644.8). LC-MS (method 1a): Rt = 2.69 (95), 645.3 ([M+H]+).

Synthesis of the amino ester 57 A soln of 56 (5.6 g, 8.66 mmol) in dry CH2Cl2 (75 mL) was treated with TFA (15 mL) at rt for 1 h. The volatiles were evaporated. Aq. workup (CH2Cl2, sat. aq.
NaHCO3 soln, sat. aq. NaCl soln; Na2SO4) of the residue gave 57 (4.93 g, quant.
yield).
Data of 57: C32H36N206(544.6). LC-MS (method la): Rt = 1.88 (93), 545.2 ([M+Hr).
Synthesis of amino acid 58 A degassed solution of ester 57 (4.7 g, 8.66 mmol) and 1,3-dimethylbarbituric acid (1.62 g, 10.4 mmol) in CH2Cl2 (73 mL) and Et0Ac (73 mL) was treated with Pd(PPh3)4 (0.3 g, 0.26 mmol) at rt for 1.5 h. The volatiles were evaporated.
The solid was suspended in Et0Ac (200 mL), filtered and washed (Et0Ac). The solid was suspended in CH2Cl2. The volatiles were evaporated. The residue was dried i.v.
to yield 58 (3.94 g, 90%).
Data of 58: C29H32N206 (504.6). LC-MS (method 1a): Rt = 1.61 (91), 505.2 ([M+H]-).
Synthesis of Ex.68 A soln of the amino acid 58 (3.45 g, 6.8 mmol) in CH2Cl2 (150 mL) was added dropwise over 2 h by syringe pump to a soln of T3P (50% in Et0Ac; 10 mL, 17.1 mmol) and i-Pr2NEt (4.7 mL, 27.4 mmol) in dry CH2Cl2 (1250 mL). Partial evaporation of the volatiles, aq. workup (sat. aq. NaHCO3 soln; Na2SO4) and FC
(CH2C12/Me0H
98.5:1.5) yielded Ex.68 (2.579, 78%).
Data of Ex.68: C29H30N205 (486.5). LC-MS (method 1d): Rt = 2.23 (95), 486.9 ([A+Fil+).
Synthesis of Ex.69 A soln of Ex.68 (2.5 g, 5.2 mmol) in Me0H (50 mL) and CH2Cl2 (25 mL) was hydrogenated for 2 h at rt and normal pressure in the presence of palladium on activated charcoal (moistened with 50% H20; 1.9 g). The mixture was filtered through a pad of celite. The solid was washed with Me0H/CH2C12 2:1. The combined filtrate and washings were concentrated to give Ex.69 (2.0 g, 98%).
Data of Ex.69: C22H24N206 (396.4). LC-MS (method 1a): Rt = 1.58 (98), 397.1 1H-NMR (DMSO-d6): 13.05 (br. s, 1 H); 8.21 (br. s, 1 H); 7.86 - 7.17 (several m, 6.33 H); 7.06 (s, 0.66 H); 6.96 (d, J = 8.2, 0.66 H); 6.90 (dd, J
= 1.9, 8.2, 0.33 H); 4.49 -4.31 (m, 1.66 H); 4.15 (s, 2 H); 3.57 (t, J = 11.8, 0.33 H);
2.91, 2.86 (2 br. s, 3 H); 2.45 - 2.20 (m, 2.33 H); 2.2 - 2.0 (m, 1.66 H); 1.15 - 1.12 (2 d, 3 H), Core 05: Synthesis of Ex.90, Ex.91 and Ex.92 (Scheme 12) Synthesis of amide 59 A mixture of acid 10-HCI (9.34 g, 31.8 mmol), amine 28-HC1 (13.1 9, 41.3 mmol), HATU (19.3 g, 51 mmol) and HOAt (6.93 g, 51 mmol) in DMF (75 mL) was cooled to 0 C, followed by the addition of i-Pr2NEt (21.6 mL, 127 mmol). The mixture was stirred for 4 h and concentrated to ca 50% of its volume. The mixture was diluted with 1 M aq. HCI soln and extracted twice with Et0Ac. The combined organic layer was washed (H20, sat. aq. NaHCO3 soln,), dried (Na2SO4), filtered and concentrated. FC
(hexane/Et0Ac 50:50 to 20:80) of the crude product afforded 59 (13.4g, 80%).
Data of 59: C28F129N307 (519.5). LC-MS (method 1a): Rt = 1.89 (98), 520.0 ([M+H]).
Synthesis of phenol 60 At 0 C 3-(dimetylamino)propylamine (12.0 mL, 95.4 mmol) was slowly added to a soln of 59 (16.53 g, 31.8 mmol) in THF (110 mL). The soln was allowed to warm to rt over 2 h. Aqueous workup (Et0Ac, 1 M aq. HCI soln, sat. aq. NaHCO3 soln;
Na2SO4) yielded 60 (14.45 g, 95%).
Data of 60: C26F127N306 (477.5). LC-MS (method la): Rt = 1.67 (97), 478.1 ([M+1-1]+).
Synthesis of the Mitsunobu product 61 The phenol 60 (4.35 g, 9.1 mmol) and the alcohol 18 (3.56 g, 11.8 mmol) were dissolved in toluene (39 mL). CMBP (3.0 mL, 11.4 mmol) was added and the mixture was heated to reflux for 0.5 h. More CMBP (0.31 mL, 1.2 mmol) was added and the mixture was refluxed for 0.5 h followed by evaporation of the volatiles and FC

(hexane/Et0Ac 50:50 to 0:100) to afford 61(5.25 g, 77%).
Data of 61: C40H49N5010 (759.8). LC-MS (method 1 a): Pt = 2.24 (92), 760.2 ([M+H]-).
Synthesis of the amino acid 63 A soln of 61 (11.8 g, 16 mmol) in THF (59 mL) and Me0H (30 mL) was treated with 2 M aq. LiOH soln (31 mL, 62 mmol) at it for 2 h. The volatiles were partially evaporated. The remaining mixture was acidified to pH ca 1 by addition of 3 M
aq.
HCI soln and repeatedly extracted with Et0Ac. The combined organic phase was dried (Na2SO4) and concentrated to afford crude acid 62 (12.6 g).
1,3-Dimethylbarbituric acid (3.29, 20.5 mmol) and acid 62 (12.5 g) were dissolved in CH2C12/Et0Ac 1:1 (300 mL). The mixture was degassed, treated with Pd(PPh3)4 (1.98 g, 1.71 mmol) and stirred at it for 2 h. The volatiles were evaporated. The residue was suspended in Et0Ac and filtered to give 63 (9.80 g, 97%).

Data of 63: C34H41N508 (647.7). LC-MS (method 1c): Rt = 1.51 (83), 648.1 ([M+H]+).
Synthesis of Ex.90 A soln of the amino acid 63 (2.0 g, 3.1 mmol) in DMF (50 mL) was added dropwise over 2 h by syringe pump to a soln of T3P (50% in Et0Ac; 9.1 mL, 15 mmol) and i-Pr2NEt (4.2 mL, 25 mmol) in dry CH2Cl2 (600 mL). Partial evaporation of the volatiles, aq. workup (sat. aq. NaHCO3 soln; Na2SO4) and FC (CH2C12/Me0H 100:0 to 97:3) yielded Ex.90 (1.18 g, 60%).
Data of Ex.90: C34H39N507 (629.7). LC-MS (method 1d): R1 = 2.00 (99), 630.0 ([M+H]). 1H-NMR (DMSO-c16): 9.68, 9.62 (2 s, 1 H); 9.18 (s, 1 H); 9.11 (s, 1 H); 8.97 (s, 1 H); 8.41 (br. s, 1 H); 7.58 (d, J = 7.5, 1 H); 7.40 (t, J = 7.9, 1 H);
7.40 -7.20 (m, 5 H); 7.17 (m, 1 H); 6.94 (d, J = 8.0, 1 H); 5.15 (d, J = 12.1, 0.5 H); 5.12 (s, 1 H); 5.01 (d, J = 12.9, 0.5 H); 4.55 - 4.15 (m, 4 H); 4.15 - 3.5 (several m, 5 H); 3.5 -3.1 (several m, 3 H); 2.11 (m, 1 H); 1.91 (m, 1 H); 1.40 (s, 9 H).
Synthesis of Ex.91 A soln of Ex.90 (200 mg, 0.32 mmol) in Me0H (5 mL) was hydrogenated for 2 h at rt and normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50% H20; 50 mg). The mixture was filtered through a pad of celite.
The solid was washed with Me0H. The combined filtrate and washings were concentrated to give Ex.91 (150 mg, 95%).
Data of Ex.91: C26H33N505 (495.6). LC-MS (method la): R1 = 1.48 (97), 496.1 ([m+H]). 1H-NMR (DMSO-c16): 9.73 (br. s, 1 H); 9.26 (t, J = 1.9, 1 H); 9.18 (d, J = 1.9, 1 H); 8.94 (d, J = 1.9, 1 H); 8.51 (s, 1 H); 7.59 (d, J = 7.7, 1 H); 7.40 (t, J = 7.9, 1 H);
7.26 (d, J = 6.5, 1 H); 6.94 (dd; J = 1.9, 8.1, 1 H); 4.5 -4.4 (m, 2 H); 4.26 (m, 1 H);
3.89 (t, J ca. 11.5, 1 H); 3.67 (dd, J = 7.2, 9.7, 1 H); 3.53 (d, J = 17.9,1 H); 3.39 (d, J
= 17.8, 1 H); 3.21 -3.08 (m, 3 H); 2.55 (m, 1 H); ca 2.45 (m, 1 H); 2.11 (m, 1 H); 1.89 (m, 1 H); 1.40 (s, 9 H).
Synthesis of Ex.92 A soln of Ex.90 (200 mg, 0.32 mmol) in dioxane (2 mL) was treated with 4 M HCI
in dioxane (2 mL) for 15 h. The volatiles were evaporated. Purification by prep.
HPLC
(method lc) afforded Ex.92-2CF3CO2H (89 mg, 37%) and Ex.93 3 CF3CO2H (34 mg, 17%).
Data of Ex.92.2 CF3CO2H: C29H31N505 (529.6, free base). LC-MS (method la): R =
1.38 (98), 530.1 ([M+H]).
Data of Ex.93-3 CF3CO2H: Cf Table 17b Core 05: Synthesis of selected advanced intermediates and final products (Scheme 12) Synthesis of Ex.94 A soln of Ex.91 (137 mg, 0.28 mmol) in DCE (4.0 mL) was cooled to 0 C. Aq.
formaldehyde soln. (36.5%; 0.104 mL, 1.38 mmol) was added followed by acetic acid (0.019 mL, 0.332 mmol) and NaBH(OAc)3 (234 mg, 1.106 mmol). The mixture was stirred at 0 C for 4 h followed by an aq. workup (CH2Cl2, sat. aq. NaHCO3 soln). FC
(CH2C12/Me0H 100:0 to 95:5) afforded Ex.94 (119 mg, 84%).
Data of Ex.94: cf. Table 17b 1H-NMR (DMSO-d6): 9.60 (br.s, 1 H); 9.21 (t, J = 1.9,1 H); 9.17 (d, J = 1.9,1 H); 8.93 (d, J = 1.9, 1 H), 8.48 (s, 1 H); 7.58 (d, J = 7.7, 1 H); 7.39 (t, J = 8.0, 1 H); 7.28 (d, J =
6.4, 1 H); 6.94 (dd, J = 1.9, 8.1, 1 H); 4.45 - 4.41 (br, m, 2 H); 4.26 (m, 1 H); 3.88 (br.
t, J ca 11.5,1 H); 3.68 (dd, J = 7.2, 9.7,1 H); 3.45(d, J = 17.6,1 H); 3.89 -3.21 (m, 3 H, signal partially superimposed by H20 signal); 3.15 (t-like m, J ca 9, 1 H);
2.62 (br.
not resolved m, 2 H), 2.37 (s, 3 H); 2.11 (m, 1 H); 1.90 (m, 1 H); 1.41 (s, 9 H).
Synthesis of Ex.95 A soln of Ex.94 (100 mg, 0.196 mmol) in dioxane (1.0 mL) was treated with 4 M
HCI-dioxane (1.0 mL) for 2 h. The volatiles were evaporated to afford Ex.953HCI
(116 mg, quant.).
Data of Ex.953HCI: cf. Table 17b Synthesis of Ex.96 At 0 C, i-Pr2NEt (0.11 mL, 0.65 mmol) was slowly added to a soln of Ex.953HCI
(97 mg, 0.19 mmol), 2-naphthaleneacetic acid (49 mg, 0.26 mmol), HATU (124 mg, 0.326 mmol) and HOAt (44 mg, 0.323 mmol) in DMF (1.0 mL). The mixture was stirred at at 0 C for 2 h and distributed between CH2Cl2 and 1 M aq. HCI soln. The organic phase was washed (sat. aq. NaCI soln), dried (Na2SO4), filtered and concentrated. FC
(CH2C12/Me0H 100:0 to 95:5) and prep. HPLC (method 1 b) afforded Ex.96.2CF3CO2H (62 mg, 41%).
Data of Ex.96: cf. Table 17b 1H-NMR (DMSO-d6): Ca. 9.7 (very br. s, 1H); 9.28 (very br. s, 1 H); 9.14 (br.
s, 1 H);
8.96 (very br. s, 1 H); 8.62 (d, J = 5.4, 1 H); 8.54 (br. s, 1 H); 8.30 (br.
s, 1 H); 7.90 -7.85 (m, 3 H); 7.77 (s, 1 H); 7.65 (d, J = 7.6, 1 H); 7.53 -7.41 (m, 4 H);
6.98 (d, J =
8.3, 1 H); 4.55 -4.33 (2 br. not resolved m, 5 H); 4.01 (t, J = 11.2, 1 H);
3.85 (br. t, J

ca 8.4, 1 H); 3.65 (br. not resolved m, 2 H); 3.63 (s, 2 H); 3.39 (br. not resolved m, 2 H); 3.11 (t, J = 9.0, 1 H); 2.89 (s, 3 H); 2.26 (m, 1 H); 2.04 (m, 1 H).
Synthesis of Ex.101 A soln of 1-naphthaleneacetic acid (43 mg, 0.23 mmol) and T3P (50% in DMF;
0.17 mL; 0.29 mmol) in DMF (0.3 mL) was added dropwise to a suspension of Ex.95-(50 mg, 0.096 mmol) in DMF (0.2 mL). The mixture was stirred at rt for 15 h followed by an aqueous workup (CHCI3, sat. aq. Na2CO3 soln; Na2SO4) and purification by prep. HPLC (method la) to afford Ex.101.2 CF3CO2H (38 mg, 49%).
Data of Ex.101-2 CF3CO2H: cf. Table 17b 11-I-NMR (DMSO-d6): 9.71 (very br. s, 1 H ); 9.26 (d, J = 1.9, 1 H); 9.13 (br.
s, 1 H);
8.93 (d, J = 1.5, 1 H); 8.68 (d, J = 5.6, 1 H); 8.52 (br. s, 1 H); 8.30 (s, 1 H); 8.10 (m, 1 H), 7.93 (m, 1 H); 7.84 (dd, J = 1.9, 7.3, 1 H); 7.66 (d, J = 7.7, 1 H); 7.57 -7.41 (m, 5 H); 6.98 (dd, J = 1.8, 8.3, 1 H); 4.55 -4.39 (2 br. not resolved m, 5 H); 4.04-3.94 (m, 3 H); 3.83 (br. t, J ca 8.5, 1 H); 3.68 (br. not resolved m, 2 H); 3.41 (br.
not resolved m, 2 H); 3.12 (t, J = 9.0, 1 H); 2.89 (s, 3 H); 2.26 (m, 1 H); 2.03 (m, 1 H).
Synthesis of Ex.103 At 4 C, Et3N (0.04 mL, 0.29 mmol) and then benzenesulfonyl chloride (17 mg, 0.096 mmol) were added to a soln of Ex.953HCI (50 mg, 0.096 mmol) in CH2Cl2 (0.5 mL).
The mixture was stirred at rt for 15 h; i-Pr2NEt (0.049 mL, 0.29 mmol) and more benzenesulfonyl chloride (17 mg, 0.096 mmol) were added. Stirring was continued for 1 h followed by an aqueous workup (CHCI3, sat. aq. Na2003 soln, Na2SO4) and purification by prep. HPLC (method la) to afford Ex.103 2 CF3CO2H (33 mg, 44%).
Data of Ex.103 2 CF3CO2H: cf. Table 17b 1H-NMR (DMSO-d6): 9.69 (br. s, 1 H); 9.24 (d, J = 1.9, 1 H); 9.09 (br. s, 1 H); 8.92 (d, J = 1.6, 1 H); 8.47 (br. s, 1 H); 8.30 (br. s, 1 H); 8.22 (br. s, 1 H); 7.90 -7.88 (m, 2 H);
7.74 -7.63 (m, 4 H); 7.41 (t, J = 7.9, 1 H); 6.93 (dd; J = 1.9, 8.2, 1 H); ca.
4.5 -4.2 (m, 4 H); 4.00 (br. not resolved m, 1 H); 3.89 (t, J ca. 11.4, 1 H); 3.69 -3.63 (m, 3 H);
3.42 (br. not resolved m, 2 H); 3.23 (dd, J = 8.4, 9.7; 1 H); 2.91 (s, 3 H);
2.02 (m, 1 H); 1.88(m, 1 H).
Synthesis of Ex.97 3-Fluorobenzaldehyde (50 mg, 0.40 mmol) was added to a soln of Ex.91 (120 mg, 0.24 mmol) in THF (1.5 mL). The soln was stirred at rt for 1 h followed by the addn of acetic acid (0.015 mL, 0.27 mmol) and NaBH(OAc)3 (154 mg, 0.73 mmol). The mixture was stirred at it for 16 h. More 3-fluorobenzaldehyde (15 mg, 0.12 mmol) was added and stirring continued. Aq. workup (CH2Cl2, sat. aq. Na2CO3 soln;
Na2SO4) and FC (CH2C12/Me0H) afforded Ex.97 (117 mg, 80%).
Data of Ex.97: cf. Table 17b Synthesis of Ex.98 A soln of Ex.97 (94 mg, 0.156 mmol) in dioxane (0.8 mL) was treated with 4 M
HCI-dioxane (0.8 mL) for 2 h. The volatiles were evaporated to afford Ex.98-3HCI
(91 mg, 95%).
Data of Ex.983HCI: cf. Table 17b Synthesis of Ex.100 A soln of Ex.98.3HCI (62 mg, 0.10 mmol) in CH2Cl2 (0.6 mL) was treated with pyridine (0.041 mL, 0.51 mmol) and acetyl chloride (16 mg, 0.2 mmol) at it for 16 h. i-Pr2NEt (0.052 mL, 0.3 mmol) and more acetyl chloride (16 mg, 0.2 mmol) were added and stirring was continued for 24 h followed by an aqueous workup (CHCI3, sat. aq.

Na2CO3 soln; Na2SO4) and purification by prep. HPLC (method la) to afford Ex.100 2 CF3CO2H (50 mg, 64%).
Data of Ex.100- 2 CF3002H: cf. Table 17b 1H-NMR (DMSO-d6): Ca. 9.5 (br. s, 1 H); 9.23 (s, 2 H); 8.96 (d, J = 1.0, 1 H);
8.45 (br.
s, 1 H); 8.17 (d, J = 6.5, 1 H); 7.62 (d, J = 7.7, 1 H); 7.42 (t, J = 7.9, 1 H); ca 7.4 (br.
not resolved m, 1 H); ca 7.35 -7.25 (br. not resolved m, 2 H); 7.15 (br. t-like m, 1 H);
6.97 (dd; J = 1.9, 8.2, 1 H); 4.52 -4.39 (m, 4 H); ca 4.2 -3.8 (br. not resolved m, 3 H); 3.90 (t, J = 11.3, 1 H); 3.71 (t-like m, 2 H); 3.49 (m, 1 H); 3.33 (br. t-like m, 1 H);
3.07 (t, J = 9.0, 1 H); 2.95 (br. not resolved m, 2 H); 2.14 (m, 1 H); 1.89 (m, 1 H); 1.81 (s, 3 H).
Core 06 /07: Synthesis of Ex.115, Ex.116 and Ex.129, Ex.130 (Scheme 13) Synthesis of the arylbromide 65 2-Bromothiophenol (11; 2.71 mL, 23 mmol) was added to a soln of 30 (5.0 g, 19.1 mmol) and CMBP (6.02 mL, 23 mmol) in toluene (50 mL). The mixture was heated to reflux for 1 h. The volatiles were evaporated. FC (hexane/Et0Ac 4:1) afforded 7.31 g, 88%).
Data of 65: C18F126BrNO4S (432.3). LC-MS (method 1c): R = 2.58 (97), 434.0/431.9 ([M+H]).

Synthesis of the biphenyl 66 Sat. aq. NaHCO3 soln (37.8 mL) was added dropwise to a soln of 65 (5.0 g, 11.6 mmol), 3-hydroxyphenylboronic acid (12, 4.79 g, 34.7 mmol) and Pd(PPh3)4 (1.34 g, 1.16 mmol) in DME (150 mL). The mixture was heated to reflux for 4 h. The volatiles were evaporated and the residue was distributed between Et0Ac and sat. aq.
Na2CO3 soln. The organic phase was repeatedly washed (sat. aq. Na2CO3 soln), dried (Na2SO4), filtered and concentrated. FC (CH2C12/Et0Ac 100:0 to 95:5) afforded 66 (3.91 g, 75%).
Data of 66: C24H31 N 05S (445.5). LC-MS (method 1a): Rt = 2.46 (94), 446.1 ([M+Hl+).
Synthesis of the phenol 68 At 0 C, TFA (11.9 mL) was slowly added to a soln of 66 (2.38 g, 5.34 mmol) in CH2Cl2 (24 mL). Stirring was continued for 1 h followed by evaporation of the volatiles. The residue was dissolved in CHCI3 and concentrated to afford 67.CF3CO2H
as a brown oil which was dissolved in CH2Cl2 (12 mL) and cooled to 0 C. i-Pr2NEt (2.73 mL, 16.0 mmol) was slowly added. Ally] chloroformate (0.63 mL, 5.88 mmol) in CH2Cl2 (12 mL) was added over 30 min. The mixture was stirred for 2 h followed by evaporation of the volatiles. Aqueous workup (Et0Ac, sat. aq. NaNC03 soln;
Na2SO4) and FC (hexane/Et0Ac 9:1 to 7:3) yielded 68 (2.02 g, 88%).
Data of 68: C23H27NO55 (429.5). LC-MS (method la): Rt = 2.29 (92), 430.1 ([1V1 FI]l=
Synthesis of the ether 69 A soln of ADDP (1.34 g, 5.31 mmol) in degassed CHCI3 (5.0 mL) was added at 0 C
to a soln of 68 (1.52 g, 3.54 mmol), Boc-D-alaninol (20; 0.93 g, 5.31 mmol) and PPh3 (1.39 g, 5.31 mmol) in CHCI3 (20 mL). The mixture was stirred at 0 C to rt for 16 h.
More Boc-D-alaninol (20; 0.93 g, 5.31 mmol) and PPh3 (1.39 g, 5.31 mmol) were added. The mixture was cooled to 0 C followed by the slow addition of ADDP
(1.34 g, 5.31 mmol) in CHCI3 (5.0 mL). The mixture was stirred at rt for 16 h. The volatiles were evaporated. The residue was suspended in Et20 and filtered. The filtrate was concentrated and purified by FC (hexane/Et0Ac 4:1 to 3:1) to afford 69 (1.6 g, 77%).
Data of 69: C31F142N2073 (586.7). LC-MS (method 1a): Rt = 2.78 (97), 587.1 ([M+H]).
Synthesis of the amino acid 71 A soln of 69 (3.2 g, 5.5 mmol) in THF (17 mL) and Me0H (17 mL) was treated at with 1 M aq. LiOH soln (6.5 mL, 6.5 mmol). The mixture was allowed to stir at 0 C to rt for 16 h. The volatiles were evaporated. The residue was distributed between Et0Ac and 0.2 M aq. HCI soln. The organic phase was dried (Na2SO4) and concentrated to afford crude acid 70 (3.02 g) which was dissolved in dioxane (12.5 mL) and treated with 4 M HCI-dioxane (7.9 mL) for 4 h. The volatiles were evaporated. The residue was taken up in CHCI3 and concentrated to afford crude 71 -NCI (2.84 g, quant. yield) which was used without further purification.
Data of 71.HCI: C25H32N205S HCI (472.6, free base). LC-MS (method 1a): Rt =
1.76 (89), 473.1 ([M+H]).
Synthesis of Ex.115 A soln of crude 71-HCI (0.94 g, 1.8 mmol) in CH2Cl2 (45 mL) was added over 2 h to a soln of T3P (50% in Et0Ac; 2.7 mL, 4.6 mmol) and i-Pr2NEt (1.3 mL, 7.4 mmol) in CH2Cl2 (1810 mL). The soln was partially concentrated, washed with sat. aq.
NaHCO3 soln, dried (Na2SO4), filtered and concentrated. FC (hexane/Et0Ac 8:2 to 1:1) gave Ex.115 (0.63 g, 75%).
Data of Ex115: C25H30N2045 (454.6). LC-MS (method 1d): R = 2.35 (95), 455.0 [M+H]-). 1H-NMR (DMSO-d6): 7.57 - 7.52 (m, 2 H); 7.38 - 7.21 (m, 5 H); 7.01 -6.95 (m, 2 H); 6.90 (d, J = 7.9, 1 H), 5.90 (m, 1 H); 5.29 (d, J = 17.2, 1 H); 5.17 (d, J =
10.0, 1 H); 4.47 - 4.45 (m, 2 H); 4.13 - 3.97 (m, 3 H); 3.82 (q, J = 6.5, 1 H); 2.60 -2.57 (m, 2 H); 1.57 - 1.09 (m, 6 H); 1.19 (d, J = 6.5, 3 H).
Synthesis of Ex.116 A soln of Ex.115 (120 mg, 0.26 mmol) in degassed Et0Ac/CH2C12 1:1 (2.1 mL) was treated at rt for 16 h with Pd(PPh3)4 (1.2 mg) and 1,3-dimethylbarbituric acid (49 mg, 0.32 mmol). The volatiles were evaporated and the residue purified by FC
(hexane/Et0Ac 50:50 to 0:100, then CH2C12/Me0H 100:0 to 90:10) to afford Ex.116 (82 mg, 83%).
Data of Ex.116: C211-126N202S (370.5). LC-MS (method la): R = 1.74 (95), 371.1 1H-NMR (DMSO-d6): 7.76 (d, J = 7.1, 1 H); 7.55 (m, 1 H); 7.37 -7.26 (m, 4 H);
7.07 (t-like m, 1 H); 6.98 (dd-like m, 1 H); 6.87 (d-like m, J ca 7.9, 1 H), 4.14 -4.01 (m, 3 H); 3.32 (t, J = 5.0, 1 H); 2.67 - 2.55 (m, 2 H); ca 2.6 (very br. s, 2 H);
1.56 (m, 1 H);
1.38 - 1.03 (m, 5 H); 1.21 (d, J = 6.3,3 H).

Synthesis of Ex.129 At 0 C, mCPBA (70%, 876 mg, 3.55 mmol) was added in portions to a soln of Ex.115 (808 mg, 1.78 mmol) in CH2Cl2 (17 mL). The mixture was stirred at 0 C to rt for 2 h and concentrated, followed by an aq. workup (Et0Ac, sat. aq. NaHCO3 soln, 1 M
aq.
Na2S203 soln; Na2SO4). FC (hexane/Et0Ac 50:50 to 0:100) gave Ex.129 (788 mg, 91%).
Data of Ex.129:C25H301\1206S (486.6). LC-MS (method la): R = 1.91 (93), 487.1 ([M+H]). 1H-NMR (DMSO-d6): 8.06 (dd, J = 1.3, 7.9, 1 H); 7.77 (dt, J = 1.4, 7.5, 1 H);
7.68 (dt, J = 1.4, 7.7, 1 H); 7.49 - 7.44 (m, 2 H); 7.39 (t, J = 8.0, 1 H);
7.09 - 7.03 (m, 3 H); 6.73 (s, 1 H); 5.88 (m, 1 H); 5.27 (d, J = 17.3, 1 H); 5.17 (d, J =
10.3, 1 H); 4.45 (d, J = 4.9, 2 H); 4.08 - 3.96 (m, 3 H); 3.75 (q-like m, J = 7.6, 1 H); 2.45 (br. m, 2 H);
1.45 - 1.01 (m, 5 H); 1.23(d, J = 6.8,3 H); 1.01 (m, 1 H).
Synthesis of Ex.130 A soln of Ex.129 (100 mg, 0.21 mmol) in degassed Et0Ac/CH2C12 1:1 (1.7 mL) was treated at rt for 3 h with Pd(PPh3)4 (1.0 mg) and 1.3-dimethylbarbituric acid (39 mg, 0.25 mmol). The volatiles were evaporated and the residue purified by FC
(hexane/Et0Ac 50:50 to 0:100, then CH2C12/Me0H 100:0 to 90:10) to afford Ex.130 (82 mg, 98%).
Data of Ex.130: C211-126N204S (402.5). LC-MS (method la): Rt = 1.48 (94), 403.0 ([M+Hp-).
Core 06: Synthesis of selected advanced intermediates and final products (Scheme 13) Synthesis of Ex.119 At 0 C, i-Pr2NEt (0.055 mL, 0.324 mmol) was slowly added to a solution of Ex.116 (40 mg, 0.108 mmol), 1-pyrrolidineacetic acid (17 mg, 0.13 mmol), HATU (62 mg, 0.162 mmol) and HOAt (22 mg, 0.162 mmol) in DMF (0.5 mL). The mixture was stirred for 2 h at 0 C, followed by an aqueous workup (Et0Ac, sat. aq. NaHCO3 soln, H20, sat. aq. NaCI soln; Na2SO4) and purification by prep HPLC (method 3) to give Ex.119 (30 mg, 57%).
Data odf Ex.119: cf. Table 18b.

Core 08 /09: Synthesis of Ex.143, Ex.144 and Ex.168, Ex.169 (Scheme 14) Synthesis of thioether 72 5-Bromopyridine-3-thiol (13; 1.0 g, 5.3 mmol) was added to a soln of alcohol 30 (1.06 g, 4.0 mmol) and CMBP (1.17 g, 4.85 mmol) in toluene (15 mL). The mixture was heated to reflux for 1 h. The volatiles were evaporated. FC (hexane/Et0Ac 4:1) of the residue gave 72 (1.35 g, 77%).
Data of 72: C17H25BrN204S (433.6). LC-MS (method 1c): Rt = 2.37 (93), 433.0/435.0 ([M+H]).
Synthesis of phenol 73 At rt, sat. aq. NaHCO3 soln (17.1 mL) was added to a soln of 72 (2.65 g, 6.1 mmol), 2-hydroxyphenylboronic acid (14; 2.53 g, 18.3 mmol) and Pd(PPh3)4 (707 mg, 0.61 mmol) in DME (78 mL). The mixture was heated to reflux for 1 h followed by an aq.
workup (Et0Ac, sat. aq. Na2CO3 soln; Na2SO4) and FC (hexane/Et0Ac 2:1 to 1:1) to afford 73(2.42 g, 88%).
Data of 73: C23H3011205S (446.6). LC-MS (method 1a): Rt = 1.82 (96), 447.1 ([M+H]-).
Synthesis of phenol 75 At 0 C, a soln of 73 (500 mg, 1.12 mmol) in CH2Cl2 (4.0 mL) was treated with TFA
(3.0 mL) for 2 h and concentrated. Aq. workup (Et0Ac, sat. aq. NaHCO3 soln;
Na2SO4) afforded crude 74 which was dissolved in CH2Cl2 (4.0 mL). The soln was cooled to 0 C. A soln of Alloc0Su (245 mg, 1.23 mmol) in CH2Cl2 (1.0 mL) was added dropwise. Stirring was continued for 2 h followed by an aq. workup (CH2Cl2, sat. aq. NaHCO3 soln; Na2SO4) and FC (hexane/Et0Ac 1:1) to yield 75 (310 mg, 64%).
Data of 75: C22H26N205S (430.5). LC-MS (method la): Rt = 1.68 (94), 431.1 ([M+H] ).
Synthesis of the ether 76 At 0 C, ADDP (967 mg, 3.83 mmol) was added in portions to a soln of alcohol 20 (672 mg, 3.83 mmol), phenol 75 (1.1 g, 2.55 mmol) and PPh3 (1.0 g, 3.83 mmol) in CHCI3 (15 mL). The mixture was stirred for 4 h at rt and concentrated. FC
(hexane/Et0Ac 4:1 to 2:1) afforded 76 (450 mg, 30%).
Data of 76: C301-141N307S (587.7). LC-MS (method la): R = 2.33 (87), 588.2 ([M+H]+).

Synthesis of the amino acid 78 At 0 C, 1 M aq. LiOH (0.67 mL, 0.67 mmol) was added to a soln of 76 (430 mg, 0.73 mmol) in THF/Me0H 2:1 (1.5 mL). The mixture was stirred at 0 C to rt for 5 h and distributed between Et0Ac and 0.2 M aq. HCI soln. The organic phase was separated, dried (Na2SO4), filtered and concentrated. FC (CH2C12/Me0H 100:0 to 80:20) gave acid 77 (288 mg) which was dissolved in dioxane (1 mL) and treated with 4 M HCI-dioxane (1.15 mL) for 6 h at rt. The volatiles were evaporated. The residue was suspended in Et0Ac, filtered and dried i.v. to afford 78-2HCI (256 mg, 64%).
Data of 78-2HCI: C24H31N3053.2HCI (473.6, free base). LC-MS (method 1c): R =
1.39 (92), 474.1 ([M+H]).
Synthesis of Ex.143 A soln of 78,2HCI (200 mg, 0.37 mmol) and i-Pr2NEt (0.125 mL, 0.73 mmol) in CH2Cl2 (5 mL) was added dropwise over 2 h (syringe pump) to a soln of T3P (50% in Et0Ac;
0.65 mL, 1.1 mmol) and i-Pr2NEt (0.188 mL, 1.1 mmol) in CH2Cl2 (177 mL). Aq.
Workup (CH2Cl2, sat. aq. NaHCO3 soln; Na2SO4) and FC (hexane/Et0Ac 50:50 to 0:100) afforded Ex.143 (105 mg, 63%).
Data of Ex.143: C24H29N304S (455.5). LC-MS (method 1d): Rt = 1.66 (98), 456.0 ([M+H]). 1H-NMR (DMSO-d6): 8.52 (d, J = 2.2, 1 H); 8.40 (d, J = 1.9, 1 H);
8.36 (s, 1 H); 8.11 (d, J = 5.5, 1 H); 7.45 - 7.39 (m, 2 H); 7.20 (d, J = 7.6, 1 H); 7.14 (d, J = 8.2, 1 H); 7.08 (t, J = 7.5, 1 H); 5.88 (m, 1 H); 5.28 (d, J = 16.5, 1 H); 5.16 (d, J = 10.4, 1 H); 4.44 (d, J = 5.2 , 2 H); 4.17 - 3.97 (m, 4 H); 3.06 (m, 1 H); 2.89 (m, 1 H); 1.85 (m, 1 H); ca 1.6 - 1.3 (m, 5 H); 1.09 (d, J = 6.3,3 H).
Synthesis of Ex.144 A degassed solution of Ex.143 (200 mg, 0.44 mmol) in degassed CH2C12/Et0Ac 1:1 (11 mL) was treated at rt for 2 h with Pd(PPh3)4 (2.0 mg) and 1,3-dimethylbarbituric acid (82 mg, 0.53 mmol). The volatiles were evaporated. FC (hexane/Et0Ac 50:50 to 0:100 and then CH2C12/Me0H 99:1 to 95:5) gave Ex.144 (128 mg, 78%).
Data of Ex.144: C201-125N302S (371.5). LC-MS (method 1a): R = 1.30 (97), 371.9 ([M+H]). 1H-NMR (DMSO-d6): 8.52 (d, J = 2.2, 1 H); 8.40 (d, J = 2.0, 1 H);
8.16 (t, J =
2.1, 1 H); 7.77 (d, J = 6.4,1 H); 7.45 - 7.39 (m, 2 H); 7.16 (d, J = 7.9,1 H);
7.07 (dt; J
= 0.8, 7.1, 1 H); 4.13 -4.04 (m, 2 H); 3.97 (br. not resolved m, 1 H); 3.21 (t-like m, 1 H); 3.08 - 2.89 (m, 2 H); 2.01 (br. s, 2 H); 1.74- 1.18 (several m, 6 H); 1.12 (d, J =
6.5, 3 H).

Synthesis of Ex.168 H202 (35% in H20; 0.043 mL; 0.49 mmol) was added to a soln of Ex.143 (32 mg, 0.07 mmol) in AcOH (1.0 mL). The mixture was stirred at rt for 20 h; after 2h and after 3 h, 16 h and 17 h more H202 (35% in H20; 0.043 mL; 0.49 mmol) had been added . The mixture was diluted with H20 and extracted with Et0Ac. The organic phase was dried (Na2SO4), filtered and concentrated to yield Ex.168 (28 mg, 82%).
Data of Ex.168: C24H29N306S (487.5). LC-MS (method la): R = 1.78 (92), 488.1 ([1V1+H]-). 1H-NMR (DMSO-d6): 8.99 (d, J = 2.2, 1 H); 8.91 (d, J = 1.9, 1 H);
8.52 (s, 1 H); 7.86 (d, J = 4.9, 1 H); 7.49 - 7.44 (m, 2 H); 7.17 - 7.08 (m, 3 H); 5.86 (m, 1 H);
5.26(d, J = 18.6, 1 H); 5.15(d, J = 9.9,1 H); 4.42 (m, 2 H); 4.11 -3.95 (m, 3 H); 3.87 (q-like m, 1 H); 3.56 (m, 1 H); 3.35 (m, 1 H); ca 1.70 (m, 1 H); ca 1.65 (m, 1 H); 1.40 -1.10 (m, 4 H); 1.06 (d, J = 6.1,3 H).
Synthesis of Ex.169 A soln of Ex.168 (2.19 g, 4.5 mmol) and 1,3-dimethylbarbituric acid (2.1 g, 13.5 mmol) in degassed Et0Ac/CH2C12 1:1(65 mL) was treated at it for 2 h with Pd(PPh3)4 (260 mg). The volatiles were evaporated and the residue purified by FC
(CH2C12/Me0H 100:0 to 95:5) to afford Ex.169 (1.81 g, quant. yield).
Data of Ex.169: C201-126N304S (403.5). LC-MS (method la): R = 1.34 (96), 403.9 ([M+H]+). 1H-NMR (DMSO-d6): 8.97 (d, J = 2.2, 1 H); 8.92 (d, J = 2.0, 1 H);
8.39 (t, J =
2.1, 1 H); 7.64 (d, J = 6.5, 1 H); 7.49 - 7.42 (m, 2 H); 7.17 (d, J = 8.0, 1 H); 7.11 (t, J
= 7.4, 1 H); 4.11 -3.97 (m, 3 H); 3.63 (m, 1 H); 3.40 (m, 1 H); 3.07 (m, 1 H);
1.98 (br.
s,2 H); 1.58 (quint, J = 7.1,2 H); 1.27 - 1.16 (m, 2 H); 1.09 (d, J = 6.0,3 H); 1.09 (m, 1 H), 0.97 (m, 1 H).
Core 10 / 11: Synthesis of the B-AB-Ac fragment 84 (Scheme 15) Synthesis of the allylester 79 Oxalyl chloride (1.8 mL, 20.4 mmol) and DMF (26 pL) were added to a suspension of 10.HCI (2.0 g, 6.8 mmol) in CHCI3 (50 mL). The mixture was stirred at it for 1 h and concentrated (at 35 C). The residue was suspended in THF (50 mL) and cooled to 0 C. Allyl alcohol (1.4 mL, 20.4 mmol) and Et3N (2.9 mL, 20.4 mmol) were added.
The mixture was stirred at it for 1 h followed by an aq. workup (Et0Ac, 1 M
aq. HCI
soln, sat. aq. NaHCO3 soln, sat. aq. NaCI soln; Na2SO4). FC (hexane/Et0Ac 3:1) yielded 79 (1.78 g, 88%).
Data of 79: C17H16N04 (297.3). LC-MS (method 1b): Rt = 1.96 (99), 298.0 ([M+H]+).

Synthesis of the phenol 80 3-Dimethylaminopropylamine (2.3 mL, 17.9 mmol) was added at rt to a soln of 79 (1.77 g, 5.9 mmol) in THF (65 mL). The soln was stirred at rt for 3 h followed by an aq. workup (Et0Ac, 1 M aq. HCI soln, sat. aq. NaHCO3 soln, sat. aq. NaCI soln;
Na2SO4) to afford 80 (1.27 g, 83%).
Data of 80: C15H13NO3(255.3). LC-MS (method la): Rt = 1.65 (91), 255.9 ([11A+Hil.
Synthesis of the arylether 81 A soln of ADDP (1.560, 6.2 mmol) in degassed CHCI3 (10 mL) was slowly added to a soln of 80 (1.26 g, 4.9 mmol), (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (21; 0.83 g, 4.12 mmol) and PPh3 (1.62 g, 6.2 mmol) in degassed (20 mL). The soln was stirred at it for 15 h followed by evaporation of the volatiles.
The residue was suspended in Et20 and filtered. The filtrate was concentrated and purified by FC (hexane/Et0Ac 4:1) to afford 81(1.78 g, 98%).
Data of 81: C25H30N205 (438.5). LC-MS (method 1a): Rt = 2.58 (98), 439.1 ([M+H]-).
Synthesis of acid 84 A soln of 81(1.76 g, 4.0 mmol) in Me0H/THF 1:1(30 mL) was treated with 2 M aq.
LiOH soln (4.0 mL, 8.0 mmol) for 1 h at it. The mixture was concentrated. The residue was distributed between Et0Ac and 1 aq. HCI soln. The organic phase was washed (sat. aq. NaCI soln), dried (Na2SO4), filtered and concentrated to give crude 82-HCI (1.5 g) which was dissolved in dioxane (15 mL) and treated with 4 M HCI-dioxane (30 mL) for 2.5 h at it. The mixture was concentrated and repeatedly treated with CHCI3 and concentrated to obtain crude 83 2HCI (1.79 g).
To a soln of crude 832HCI (1.24 g) in THF (11 mL) was added 2 M aq NaOH soln (5.3 mL). The mixture was cooled to 0 C. A soln of ally! chloroformate (0.34 mL, 3.2 mmol) in THF (5 mL) was added dropwise over 30 min (syringe pump). Stirring was continued for 30 min followed by an aq. workup (CH2Cl2, 1 M aq. HCI soln;
Na2SO4) and purification by prep. HPLC (method 1d) to yield 84.CF3CO2H (0.93 g, 67%).
Data of 84.CF3CO2H: C21H22N205-CF3CO2H (382.4, free form). LC-MS (method la):
Rt= 1.80 (99), 383.0 ([M+Hr). 11-I-NMR (DMSO-d6): ca 13.5 (br. s, 1 H); 9.12 (s, 1 H);
9.06 (d, J = 1.9, 1 H); 8.48 (s, 1 H); 7.46 - 7.34 (m, 3 H); 7.06 (d, J = 7.4, 1 H); 5.92 (m, 1 H); 5.31 - 5.15 (m, 2 H); 4.61 -4.48 (m, 2 H); 4.23 -4.02 (m, 3 H); 3.37-3.35 (m, 2 H); ca 2.1 - 1.8 (m, 4 H).

=

Core 10: Synthesis of Ex.193a,c-h and Ex.194b (Scheme 15) Procedure C.1:
General Procedure for the synthesis of Ex.193a-h and Ex.194b (Scheme 15) 1. Synthesis of resins 85a-h: Immobilisation of Fmoc-AA1-0H
2-Chlorotrityl chloride resin (matrix: copoly(styrene-1% DVB), 100 ¨ 200 mesh, loading: 1.3 mmol/g; 10 g, 13 mmol) was suspended in dry CH2Cl2 (100 mL), shaken for 50 min and filtered. The resin was suspended in dry CH2Cl2 (80 mL). A soln of Fmoc-AA1-0H (10.3 mmol) and i-Pr2NEt (4.4 mL, 26 mmol) in DMF (20 mL) was added. The mixture was shaken at rt for 2.7 h with N2 bubbling through. The resin was filtered and washed (CH2Cl2, DMF, CH2Cl2). Capping: The resin was shaken in CH2C12/Me0H/i-Pr2NEt 15:2:3 (100 mL) for 0.5 h and filtered. The capping step was repeated twice. The resin was filtered, washed (CH2Cl2, DMF, CH2Cl2, Me0H) and dried i.v. to afford resin 85.
Chlorotrityl- Yield /
Resin Fmoc-AA1-0H
chlorid resin Loading (mass increase) 85a,h 5 g Fmoc-133-homoPhe-OH 6.79 g / 0.72 mmol/g 85b,e,f,g 10 g Fmoc-NMe-133-homoDAla-OH 13.0 g /0.78 mmol/g 85c,d 10 g Fmoc-13-Ala-OH 12.5 g /0.73 mmol/g 2. Synthesis of Ex.193a,c-h and Ex.194b Fmoc Cleavage: The resin 85 (90 - 110 mg, ca 70 pmol) was swollen, in DMF (1 mL) for 1 h and filtered. Then it was suspended in a soln of 2%v/v DBU in DMF (1 mL), shaken for 10 min, filtered off and washed (DMF). The deprotection step was repeated once. The resin was filtered and washed (DMF).
Coupling of Fmoc-AA2-0H: The resin 86 was suspended in DMF (1 mL). i-Pr2NEt (280 pmol), Fmoc-AA2-0H (140 pmol) and HATU (140 pmol) were added. The mixture was shaken for 40 min, filtered and washed (DMF). The coupling step was repeated once. The resin 87 was filtered and washed (DMF).
Fmoc Cleavage: The resin was treated with 2%v/v DBU in DMF (1 mL) as described aboveto yield resin 88.
Coupling of Alloc-protected amino acid 84: The resin 88 was suspended in DMF
(1mL)1). i-Pr2NEt (560 pmol), 84 (35 mg, 70 pmol) and PyBOP (140 pmol) were added. The mixture was shaken for 1 h and filtered. The resin was washed (DMF).

The coupling step was repeated once. The resin 89 was filtered and washed (DMF, CH2Cl2).
Alloc Cleavage: The resin 89 was suspended in CH2Cl2 (1 mL). Phenylsilane (0.18 mL; 1.45 mmo1)2) and Pd(PPh3)4 (8 mg, 7 pmol) were added. The mixture was shaken for 15 min and filtered. The deprotection step was repeated once. The resin 90 was filtered and washed (CH2Cl2, DMF, Me0H, CH2Cl2).
Release of the cyclization precursor: The resin 90 was treated with HFIP/CH2C12 2:3 (1 mL) for 30 min, filtered and washed (CH2Cl2). The cleavage step was repeated once. The combined filtrates and washings were concentrated and dried i.v. to afford crude 91a-h.
Ring closure and cleavage of side chain protective groups: Crude 91 was dissolved in dry DMF (4 mL)3) and i-Pr2NEt (96 pL; 560 pmol) was added. This soln was then added dropwise to a soln of FDPP (40 mg, 105 pmol) in DMF (20 mL)3). The soln was stirred at rt for 15 h and the volatiles were evaporated. The residue was treated with sat. aq. Na2CO3 soln (4 mL) and extracted with CHCI3 (9 mL). The organic layer was filtered through a pad of MgSO4. The filtrate was concentrated and purified by prep.
HPLC to afford Ex.193a,c-h.
Crude Ex.193b was dissolved in CH2Cl2 (0.7 mL) and treated with TFA (0.3 mL) at rt for 3 h. The volatiles were evaporated and the residue was purified by prep.
HPLC to give Ex.194b.
1) Ex.193c,d: Coupling of 84 was performed in DMF/NMP 6:1 Ex.193c,d: 0.09 mL / 0.7 mmol Phenylsilane was used Ex.193c,d: Ring closure was performed in a total volume of 12 mL of DMF
Purification methods applied, yields, LC-MS data and systematic names of Ex.193a,c-h and Ex.194b are indicated in Table 22.
Ex.193a: 1H-NMR (DMSO-d6): 9.21 (d, J = 2.1, 1 H); 8.80 (t, J = 2.0, 1 H);
8.64 (d, J =
1.8, 1 H); 8.50 (d, J = 9.0, 1 H); 8.30 (s, 1 H); 7.65 (d, J = 7.7, 1 H); 7.40 (t, J = 7.9, 1 H); 7.30- 7.10 (m, 5 H); 6.94 (dd, J = 1.8, 8.2, 1 H); 5.23 (q, J = 7.2, 1 H);
4.50 (d, J =
11.6, 1 H); 4.36 -4.26 (m, 2 H); 3.82 (t, J = 11.2, 1 H); 3.20- 3.17 (m, 2 H);
2.99 -2.70 (m, 2 H); 2.81 (s, 3 H); ca 2.50 (m, 2 H; superimposed by DMSO-d signal);
2.09 - 1.77 (m, 4 H); 1.34 (d, J = 7.2, 3 H).
Ex.194b: 1H-NMR (DMSO-d6, addition of D20): Two sets of signals were observed;

ratio 9:1; signals of major isomer: 9.17 (d, J = 2.0, 1 H); 8.64 (s, 1 H);
8.59 (d, J = 1.7, 1 H); 8.09 (s, 1 H); 7.57 (d, J = 7.8, 1 H); 7.40 (t, J = 7.9, 1 H); 6.93 (dd, J = 1.6, 8.2, 1 H); 5.54 (t-like m, 1 H); 4.56 -4.53 (m, 2 H); 4.31 (m, 1 H); 3.68 (t, J =
11.3, 1 H);

3.55 (br. t-like m, 1 H); 3.36 (br. q-like m, 1 H); 2.81 (s, 3H); 2.80 (s, 3 H); 2.62 - 2.60 (m, 2 H); 2.31 -2.27 (m, 2 H); ca 2.1 -1.75 (m, 6 H); 1.12 (d, J = 6.8; 3 H).
Core 11: Synthesis of Ex.195a,b,e-h,j; Ex.196c,i,k and Ex.197d (Scheme 16) Procedure C.2:
General Procedure for the synthesis of Ex.195a,b,e-h,j; Ex.196c,i,k and Ex.197d (Scheme 16) 1. Synthesis of resins 135a-k: Immobilisation of Fmoc-AA1-0H
2-Chlorotrityl chloride resin (matrix: copoly(styrene-1% DVB), 100 - 200 mesh, loading: 1.3 mmol/g; 10 g, 13 mmol) was suspended in dry CH2Cl2 (100 mL), shaken for 50 min and filtered. The resin was suspended in dry CH2Cl2 (80 mL). A soln of Fmoc-AA1-0H (10.3 mmol) and i-Pr2NEt (4.4 mL, 26 mmol) in DMF (20 mL) was added. The mixture was shaken at rt for 2.7 h with N2 bubbling through. The resin was filtered and washed (CH2Cl2, DMF, CH2Cl2). Capping: The resin was shaken in CH2C12/Me0H/i-Pr2NEt 15:2:3 (100 mL) for 0.5 h and filtered. The capping step was repeated twice. The resin was filtered, washed (CH2Cl2, DMF, CH2Cl2, Me0H) and dried i.v. to afford resin 135, Chlorotrityl- Yield /
Resin Fmoc-AA1-0H
chlorid resin Loading (mass increase) 135a-d 10 g Fmoc-NMe-133-homoDAla-OH 13.0 g /0.78 mmol/g 135e,f,h,j 1 g Fmoc-Sar-OH 1.34 g /
0.80 mmol/g 135g 1 g Fmoc-Gly-OH 1.22 g /
0.70 mmol/g 135i 1 g Fmoc-Ala-OH 1.28 g /
0.67 mmol/g 135k 2 g Fmoc-DAla-OH 2.35 g /
0.71 mmol/g 2. Synthesis of Ex.195a,b,e-h,j; Ex.196c,i,k and Ex.197d Fmoc Cleavage: The resin 135 (90 - 107 mg, ca 70 pmol) was swollen in DMF (1 mL) for 1 h and filtered. Then it was suspended in a soln of 2%v/v DBU in DMF (1 mL), shaken for 10 min filtered and washed (DMF). The deprotection step was repeated once. The resin 136 was filtered and washed (DMF).
Coupling of Fmoc-AA2-0H: The resin 136 was suspended in DMF (1 mL). i-Pr2NEt (280 pmol), Fmoc-AA2-0H (140 pmol) and HATU (140 pmol) were added. The mixture was shaken for 40 min, filtered and washed (DMF). The coupling step was repeated once. The resin 137 was filtered and washed (DMF).

Fmoc Cleavage: The resin 137 was treated with 2%v/v DBU in DMF (1 mL) as described above to afford resin 138.
Coupling of Fmoc-AA3-0H: The resin 138 was suspended in DMF (1 mL). i-Pr2NEt (280 pmol), Fmoc-AA3-0H (140 pmol) and HATU (140 pmol) were added. The mixture was shaken for 40 min, filtered and washed (DMF). The coupling step was repeated once. The resin 139 was filtered and washed (DMF).
Fmoc Cleavage: The resin 139 was treated with 2%v/v DBU in DMF (1 mL) as described above to afford resin 140.
Coupling of AIloc-protected amino acid 84: The resin 140 was suspended in DMF
(1mL). i-Pr2NEt (560 pmol), 84 (36 mg, 84 pmol) and PyBOP (140 pmol) were added.
The mixture was shaken for 1 h and filtered. The resin 141 was washed (DMF).
The coupling step was repeated once. The resin was filtered and washed (DMF, CH2Cl2).
Alloc Cleavage: The resin 141 was suspended in CH2Cl2 (1 mL). Phenylsilane (0.18 mL; 1.4 mmol) and Pd(PPh3)4 (8 mg, 7 pmol) were added. The mixture was shaken for 15 min and filtered. The deprotection step was repeated once. The resin 142 was filtered and washed (CH2Cl2, DMF, Me0H, CH2Cl2).
Release of the cyclization precursor: The resin 142 was treated with HFIP/CH2C12 2:3 (1 mL) for 30 min, filtered and washed (CH2Cl2). The cleavage step was repeated once. The combined filtrates and washings were concentrated, taken up in CH3CN
(3 mL), concentrated and dried i.v. to afford crude 143a-k.
Ring closure and cleavage of side chain protective groups: Crude 143 was dissolved in a soln of i-Pr2NEt (98 pL; 570 pmol) in dry DMF (4 mL). This soln was then added dropwise to a soln of FDPP (41 mg, 106 pmol) in DMF (20 mL). The soln was stirred at rt for 5 h and the volatiles were evaporated. The residue was treated with sat. aq.
Na2CO3 soln (4 mL) and extracted with CHCI3 (9 mL). The organic layer was filtered through a pad of MgSO4. The filtrate was concentrated to afford crude Ex.195a-k.
Crude products Ex.195a,b,e-h,j were purified by prep. HPLC to afford Ex.195a,b,e-h,j.
A soln of crude product Ex.195c,d,i or k in TFA/CH2Cl2 3:7 (1 mL) was stirred at rt for 3 h. The volatiles were evaporated. The residue was dissolved in CH2Cl2, concentrated, dried i.v. and purified by prep. HPLC to afford Ex.196c,i,k or Ex.197d, respectively.
Purification methods applied, yields, LC-MS data and systematic names of Ex.195a, b,e-h,j; Ex.196c,i,k and Ex.197d are indicated in Table 23a.

Ex.195b: 1H-NMR (CD30D): 9.16 (d, J = 2.1, 1 H); 8.97 (t, J = 2.1, 1 H); 8.94 (d, J =
2.0, 1 H); 7.57 - 7.39 (m, 3 H); 7.00 (m, 1 H); 5.23 (m, 1 H); ca 4.8 (1 H, superimposed by HDO signal); 4.40 (d, J = 16.8, 1 H); ca. 4.4 (br. m, 1 H), 4.28 (dd; J
= 3.8, 8.1, 1 H); 3.73 (d, J = 16.8, 1 H); 3.77 - 3.60 (m, 3 H); 2.98 (s, 3 H); 2.65 (dd, J
= 2.4, 13.6, 1 H); 2.37 (t, J = 12.8, 1 H); 2.20 -2.02 (m, 4 H); 1.46 (d, J =
7.0,3 H);
1.15 (d, J = 7.0,3 H).
Ex.195h: 1H-NMR (CD30D): Two sets of signals were observed; ratio 1:1; 9.06(d, J =
2.0, 0.5 H); 9.00 (d, J = 2.0, 0.5 H); 8.97 (d, J = 1.9, 0.5 H); 8.84 (d, J =
1.9, 0.5 H);
8.72 (t, J = 2.1, 0.5 H); 8.50 (t, J = 2.1, 0.5 H); 7.88 (s, 0.5 H); 7.65 (s, 0.5 H); 7.50 -7.35 (m, 2 H); 7.32 -7.19 (m, 3.5 H); 7.09 -6.93 (m, 2.5 H); 5.89 (d, J =
16.7, 0.5 H);
5.26 - 5.20 (q-like m, 1 H), 4.79 (q, J = 7.2, 0.5 H); 4.65 (dd, J ca 4.7, 11.8, 1 H); 4.51 (dt-like m, 1 H); 4.50 (br. m, 0.5 H); 4.05 (d, J = 7.2, 1 H); 3.90 (t, J =
9.6, 0.5 H); 3.75 -3.44 (m, 3.5 H); 3.23 (dd, J = 4.5, 13.9, 0.5 H); 3.12 - 3.05 (m, 1 H); 2.98 (s, 3 H);
2.24 -2.04 (m, 4 H); 1.43 (d, J = 7.0, 1.5 H); 1.36 (d, J = 7.2, 1.5 H).
Core 12: Synthesis of Ex.198, Ex.199 and Ex.200 (Scheme 17) Synthesis of the Mitsunobu product 144 CMBP (9.9 mL, 38 mmol) was added to a soln of the hydroxypyridine 93 (4.32 g, mmol) and the alcohol 16 (6.5 g, 22 mmol) in toluene (200 mL). The mixture was heated to 80 C for 1 h. The volatiles were evaporated. FC (hexane/Et0Ac/Me0H
gradient) afforded 144 (8.60 g, 90%).
Data of 144: C27H33N307 (511.6). LC-MS (method la): Rt = 1.91 (98), 512.3 ([M+H]+).
Synthesis of the carboxylic acid 145 A soln of the ester 144 (6.56 g, 13 mmol) in Me0H (23 mL), THF (92 mL) and H20 (23 mL) was treated with Li0H.H20 (1.6 g, 38 mmol) at rt for 16 h. H20 (50 mL) was added followed by 1 M aq. HCI soln (100 mL). The mixture was repeatedly extracted with Et0Ac. The combined organic phases were washed (sat. aq. NaCI soln), dried (Na2SO4), filtered and concentrated to give 145 (6.19 g, 96%).
Data of 145: C26H31N307 (497.5). LC-MS (method 1a): Rt = 1.62 (97), 498.0 ([M+H]).
Synthesis of amide 146 A mixture of acid 145 (6.19 g, 12 mmol), amine 28.HCI (3.6 g, 11 mmol), and HATU
(5.7 g, 15 mmol) was dissolved in DMF (197 mL), followed by the addition of i-Pr2NEt (6.6 mL, 39 mmol). The mixture was stirred for 2 h. The mixture was diluted with sat.

aq. Na2CO3 soln and extracted with CH2Cl2. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was dissolved in Et0Ac, washed (H20, sat. aq.
NaCI soln), dried (Na2SO4), filtered and concentrated. FC (hexane/Et0Ac 1:3) afforded 146 (7.1g, 74%).
Data of 146: C40H49N5010 (759.8). LC-MS (method la): Rt = 2.04 (92), 760.1 ([M+HP-).
Synthesis of the carboxylic acid 147 A soln of the ester 146 (7.07 g, 9.3 mmol) in Me0H (57 mL), THF (171 mL) and (57 mL) was treated with Li0H.H20 (1.2 g, 28 mmol) at rt for 16 h. The mixture was poured onto ice / 1 M aq. HCI soln (50 mL) and repeatedly extracted with Et0Ac. The combined organic phases were washed (sat. aq. NaCI soln), dried (Na2SO4), filtered and concentrated to give 147 (6.8 g, quant. yield).
Data of 147: C3811451%010 (731.8). LC-MS (method 1c): Rt = 1.81 (94), 731.9 ([M+H]).
Synthesis of amino acid 148 A degassed solution of ester 147 (6.8 g, 9.3 mmol) and 1,3-dimethylbarbituric acid (4.4 g, 28 mmol) in CH2Cl2 (67 mL) and Et0Ac (68 mL) was treated with Pd(PPh3)4 (0.54 g, 0.46 mmol) at rt for 2 h. The volatiles were evaporated. FC
(CH2C12/Me0H
99:1 to 80:20) afforded 148 (5.6 g, 93%).
Data of 148: C34H41N508 (647.7). LC-MS (method 1a): R = 1.45 (91), 648.0 ([M+H]-).
Synthesis of Ex.198 A solution of 148 (1.08 g, 1.7 mmol) and i-Pr2NEt (0.86 mL, 5.0 mmol) in dry DMF (40 mL) was added over 3 h (syringe pump) to a soln of HATU (1.27 g, 3.33 mmol) in DMF (1620 mL). The volatiles were evaporated. Aq. Workup (Et0Ac, sat. aq.
NaHCO3 soln, H20, sat. aq. NaCI soln; Na2SO4) and FC (Et0Ac/Me0H 95:5) afforded Ex.198 (0.65 g, 62%).
Data of Ex.198: C34H39N507 (629.7). LC-MS (method 1d): Rt = 1.61 (99), 630.3 ([M+Hy). 1H-NMR (DMSO-d6): Three sets of broad signals were observed; 8.44 (br.
d, J ca 3.7, 0.5 H); 8.32, 8.28 (2 d, J = 3.8, 3.9, 0.5 H); 7.86 -7.18 (m, 13 H); 5.12 -4.83 (m, 2 H); 4.59 - 3.46 (several m, 7 H); 3.32 - 2.72 (several m, 5 H);
2.40 -2.25 (m, 1 H), 2.15 - 1.90 (m, 1 H); 1.40, 1.39 (2 s, 9 H).
Synthesis of Ex.199 A soln of Ex.198 (0.85 g, 1.34 mmol) in dioxane (17 mL) was treated with 4 M
HCI
dioxane soln (17 mL) for 1 h at rt. The volatiles were evaporated. The residue was suspended in Et20, filtered, washed with Et20 and dried to afford Ex.199.2HCI
(836 mg; quant. yield).
Data of Ex.199=2 HCI: C29H31N505-2 HCI (529.6, free base). LC-MS (method 2c):
Rt =
1.40 (94), 530.2 ([M+H]).
Synthesis of Ex.200 A soln of Ex.198 (1.2 g, 1.91 mmol) in Me0H (40 mL) was hydrogenated for 2 hat rt and normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50% H20; 250 mg). The mixture was filtered through a pad of celite.
The solid was washed with Me0H. The combined filtrate and washings were concentrated to give Ex.200 (0.87 g, 92%).
Data of Ex.200: C26H33N505 (495.6). LC-MS (method la): Rt = 1.15 (97), 496.2 ([M+Hr). 1H-NMR (DMSO-d6): two sets of signals were observed; 8.38 (br. s, 0.3 H);
8.33 (d, J = 4.2, 0.7 H), 7.75 - 7.41 (m, 7 H), 7.18 (br. s, 1 H); 4.20 - 4.13 (m, 2 H);
3.93 - 3.87 (t-like m, 2 H); 3.76 -3.73 (d-like m, 1 H); 3.14 -2.70 (several m, 4 H);
2.45 -2.30 (m, 2 H), 2.01 (d, J = 15.9, 1 H), 1.85 (br. not resolved m, 1 H);
1.70 (d-like m, 1 H); 1.41, 1.37 (2 s, 9 H).
Core 13- 15: Synthesis of the common precursor 151 (Scheme 18) Synthesis of the amide 149 A soln of 98 (7.96 g, 33.4 mmol), 129.HCI (7.19 g, 36.8 mmol) and BOP (16.3 g, 36.8 mmol) in DMF (120 mL) was cooled to 0 C. i-Pr2NEt (22.7 mL, 134 mmol) was slowly added and stirring was continued for 30 min. Aqueous workup (Et0Ac, aq. 1 M
HCI
soln, sat. aq. NaHCO3 soln, sat. aq. NaCI soln; Na2SO4) followed by FC
(hexane/Et0Ac 2:1) afforded 149 (10.8 g, 85%).
Data of 149: C18H18FN05S (379.4). LC-MS (method la): Rt = 1.98 (90), 380.2 ([M+Hy) Synthesis of the amine 151 A suspension of phenol 149 (8.79 g, 23.2 mmol), alcohol 16 (8.35 g, 27.8 mmol) and PPh3 (9.11 g, 34.8 mmol) in benzene (278 mL) was degassed and cooled to 0 C.
DEAD (40% in toluene; 15.9 mL, 34.8 mmol) was added dropwise. The mixture was stirred at it for 16 h and concentrated. The residue was suspended in Et20 and filtered. The filtrate was concentrated and purified by FC (hexane/Et0Ac, Et3N
66:33:1) to give 150 (15.4 g).

A degassed soln of 150 (15.4 g) and 1,3-dimethylbarbituric acid (5.45 g, 34.9 mmol) in CH2Cl2 (150 mL) and Et0Ac (450 mL) was treated with Pd(PPh3)4 (0.67 g, 0.58 mmol) at rt for 1 h. Aqueous workup (Et0Ac, sat.aq. NaHCO3 soln, sat. aq. NaCI

soln; Na2SO4) and FC (Et0Ac, then CH2C12/Me0H 95:5) afforded 151 (8.18 g, 61%).
Data of 151: C28H36FN307S (577.6). LC-MS (method la): Rt = 1.87 (96), 578.4 ([1\/1+FI]) Core 13: Synthesis of Ex.220 , Ex.221 and Ex.222 (Scheme 18) Synthesis of amide 152 At 0 C, acryloyl chloride (0.37 mL, 4.57 mmol) was slowly added to a soln of 151 (2.2 g, 3.81 mmol) and i-Pr2NEt (0.78 mL, 4.57 mmol) in CH2Cl2 (33 mL). The mixture was stirred for 0.5 h followed by an aqueous workup (CH2Cl2, 0.1 M aq. HCI soln, sat. aq.
NaHCO3 soln, sat. aq. NaCI soln; Na2SO4) and FC (hexane/Et0Ac 1:1 to 3:7) to afford 152 (2.21 g, 91%).
Data of 152: C311-138FN3085 (631.7). LC-MS (method 4a): R = 1.60 (94), 632.1 (EM Hi) Synthesis of Ex.220 The catalyst Umicore M72 SIMes (RD) (64 mg, 0.075 mmol) was added in one portion to a degassed solution of 152 (240 mg, 0.38 mmol) in toluene (380 mL) and heated to 100 C for 0.5 h. The mixture was cooled to rt. More Umicore M72 SIMes (RD) catalyst (64 mg) was added and the mixture was heated to 100 C for 30 min;
this operation was repeated once again. 2-Mercaptonicotinic acid (59 mg, 0.38 mmol) was added and the heating to 100 C was continued for 1 h. The mixture was concentrated. Aqueous workup (Et0Ac, sat. aq. NaHCO3 soln; Na2SO4) and FC
(hexane/Et0Ac 50:50 to 0:100) followed by prep. HPLC (method 3) afforded Ex.220 (42 mg, 18%).
Data of Ex.220: C29F134FN308S (603.6). LC-MS (method If): Rt = 2.18 (89), 604.0 ([M+1-1]+) Synthesis of Ex.221 A soln of Ex.220 (0.49 g, 0.8 mmol) ) in Me0H (80 mL) was hydrogenated for 2 h at rt and normal pressure in the presence palladium hydroxide on activated charcoal (moistened with 50% H20; 304 mg). The mixture was filtered through a pad of Na2SO4 and celite. The solid was washed with CH2C12/Me0H 1:1 (300 mL). The combined filtrate and washings were concentrated to give Ex.221 (025 g, 51%).
Data of Ex.221: C29H36FN3085 (605.7). LC-MS (method 2f): Rt = 2.43 (90), 606.2 ([M+H]). 1H-NMR (CDCI3): 8.67 (d, J = 1.2, 1 H); 8.01 (s, 1 H); 7.69 (d, J =
1.2, 1 H);
7.52 (d, J = 8.5, 1 H); 6.98 (d, J = 8.7, 1 H); 6.55 (td, J = 2.2, 10.2, 1 H);
4.97 (td, J =
2.9, 8.7, 1 H); 4.82 (br. m, not resolved, 1 H); 4.69 (d-like m, 1 H); 4.61 (br. not resolved m, 1 H); 4.31 -4.22 (m, 2 H); 4.04 -3.90 (m, 3 H); 3.80 (s, 3 H);
3.74 (dd, J
= 2.8, 10.8, 1 H); 3.65 (m, 1 H); 3.46 (m, 1 H); 2.53 -2.41 (m, 3 H); 2.02-1.88 (m, 3 H); 1.48 (s, 9 H).
Synthesis of Ex.222 A soln of Ex.221 (233 mg. 0.39 mmol) in dioxane (1 mL) was treated with 4 M
HCI in dioxane (5 mL) for 2 h at rt. The volatiles were evaporated. The residue was suspended in Et20, filtered and dried i.v. to afford Ex.222 HCI (180 mg, 86%).
Data of Ex.222.HCI: C24H28FN306S (505.6, free base). LC-MS (method 1d): Rt =
1.55 (92), 506.2 ([M+Hy).
Core 14: Synthesis of Ex.227, Ex.228 and Ex.229 (Scheme 18) Synthesis of amide 153 At 0 C, i-Pr2NEt (2.2 mL, 13.0 mmol) was added dropwise to a soln of 151 (2.5 g, 4.3 mmol), but-3-enoic acid (0.48 g, 5.6 mmol), HATU (2.47 g, 6.5 mmol) and HOAt (0.88 g, 6.5 mmol) in DMF (60 mL). The mixture was stirred for 1.5 h at 0 C followed by an aqueous workup (Et0Ac, 1 M aq. HCI soln, sat. aq. NaHCO3 soln, sat. aq. NaCI
soln;
Na2SO4) and FC (hexane/Et0Ac 2:1 to 1:2) to give 153 (2.36 g, 84%).
Data of 153: C32H40FN3085 (645.7). LC-MS (method 4b): Rt = 1.67 (96), 646.2 ([1\A-F1-1]+).
Synthesis of Ex.227 A solution of 153 (110 mg, 0.17 mmol) and the catalyst Umicore M72 SIMes (RD) (58 mg, 0.068 mmol) in CH2Cl2 (70 mL) was degassed and heated to reflux for 2 h.
The mixture was allowed to cool to rt. 2-Mercaptonicotinic acid (106 mg, 0.68 mmol) was added. The mixture was heated to reflux for 1 h. The mixture was washed with sat.
aq. NaHCO3 soln. The organic phase was dried (Na2SO4), filtered and concentrated.
The crude product was purified by prep. HPLC (method 3) to afford Ex.227 (56 mg, 53%).

Data of Ex.227: C301-136FN308S (617.7). LC-MS (method 1d): R1 = 2.32 (87), 618.2 ([M+H]). 1H-NMR (DMSO-d6): 8.38 (s, 1 H), 8.27 - 8.24 (m, 2 H); 7.90 (s, 1 H);
7.28 -7.18 (m, 2 H); 6.70 (td, J = 2.1, 10.6, 1 H); 5.97 (td, J = 5.9, 15.8, 1 H);
5.66 (td, J =
4.6, 15.7, 1 H); 4.75 -4.63 (m, 2 H); 4.31 (br. not resolved m, 1 H); 4.06 -3.67 (m, 7 H); 3.67 (s, 3 H); 3.24 (dd, J = 6.4, 10.5, 1 H); 3.11 (br. m, 2 H); 2.30 (m, 1 H); 1.92 (m,1 H); 1.39 (s, 9 H).
Synthesis of Ex.228 Trimethyltin hydroxide (263 mg; 1.46 mmol) was added to a solution of Ex.227 (300 mg, 0.49 mmol) in DCE (15 mL). The mixture was heated to 80 C for 16 h, followed by aqueous workup (CH2Cl2, 1 M aq. HCI soln, sat. aq. NaCI soln; Na2SO4) to afford Ex.228 (350 mg, containing tin salts). An analytical sample was purified by prep. RP-HPLC (method 2a) followed by aqueous extraction (CH2Cl2, 1 M aq. HCI soln;
Na2SO4) to give Ex.228 (13 mg).
Data of Ex.228: C29H34FN308S (603.6). LC-MS (method 1a): R = 2.17 (92), 604.0 ([M+Hr-).
Synthesis of Ex.229 A soln of Ex.227 (287 mg, 0.46 mmol) in dioxane (5 mL) was treated with 4 M
HCI in dioxane (5 mL) for 5 h at it and concentrated. The residue was suspended in Et20 and filtered to afford Ex.229.HCI (240 mg, 93%).
Data of Ex.229.HCI: C26H28FN306S.HCI (517.6, free base). LC-MS (method 1a): Rt =
1.49 (92), 518.1 ([M+H]). 1H-NMR (DMSO-d6): 8.38 (br. s, 4 H), 8.28 (s, 1 H);
8.22 (d, J = 8.0, 1 H); 7.82 (s, 1 H); 7.29 (d, J = 9.4, 1 H); 6.73 (d, J = 10.6, 1 H); 5.98 (td, J = 6.0, 15.6, 1 H); 5.69 (td, J = 4.8, 15.8, 1 H); 4.74 -4.65 (m, 2 H); 4.39 (m, 1 H);
4.04 - 3.85 (m, 5 H); 3.85 -3.65 (m, 2 H); 3.67 (s, 3 H); 3.44 (dd, J = 7.1, 10.5, 1 H);
3.14 (d, J = 5.6, 2 H), 2.50 (m, 1 H); 2.04 (m, 1 H).
Core 15: Synthesis of Ex.242, Ex.243 and Ex.244 (Scheme 18) Synthesis of Ex.242 A soln of Ex.227 (1.5 g, 2.4 mmol) ) in Me0H (75 mL) was hydrogenated for 2.5 h at it and normal pressure in the presence of 5% palladium on activated charcoal (moistened with 50% H20; 300 mg). The mixture was filtered through a pad of celite.
The solid was washed with Me0H. The combined filtrate and washings were concentrated. FC (hexane/Et0Ac 1:2) gave Ex.242 (1.37 g, 91%).

Data of Ex.242: C301-138FN308S (619.7). LC-MS (method la): R = 2.47 (92), 620.0 ([M+H]). 1H-NMR (DMSO-d6): 8.51 (d, J = 1.1, 1 H); 8.29 (d, J = 1.1, 1 H);
8.07 (d, J
= 7.9, 1 H); 7.95 (s, 1 H); 7.30 -7.26 (m, 2 H), 6.70 (td, J = 2.1, 10.5, 1 H); 4.70 (m, 1 H); 4.60 (br. dd, 1 H); 4.29 (br. not resolved m, 1 H); 4.04 - 3.67 (m, 5 H);
3.67 (s, 3 H); 3.48 (br. not resolved m, 2 H); 3.28 (m, 1 H); 2.38 -2.23 (m, 3 H); 1.91 (m, 1 H), 1.77 (m, 1 H); 1.68 - 1.51 (m, 3 H); 1.39 (s, 9 H).
Synthesis of Ex.243 Trimethyltin hydroxide (175 mg; 0.97 mmol) was added to a solution of Ex.242 (200 mg, 0.32 mmol) in DCE (10 mL). The mixture was heated to 80 C for 16 h, followed by aqueous workup (CH2Cl2, 1 M aq. HCI soln, sat. aq. NaCI soln; Na2SO4) to afford Ex.243 (236 mg, containing tin salts). An analytical sample was purified by prep. RP-HPLC (method 2a) followed by aqueous extraction (CH2Cl2, 1 M aq. HCI soln;
Na2SO4) to give Ex.243 (14 mg).
Data of Ex.243: C29H36FN308S (605.7). LC-MS (method 1a): Rt = 2.27 (97), 606.2 ([M+H]).
Synthesis of Ex.244 A soln of Ex.242 (265 mg, 0.43 mmol) in dioxane (5 mL) was treated with 4 M
HCI in dioxane (5 mL) for 6 h at rt and concentrated. The residue was taken up in CHCI3 and concentrated to afford Ex.244.HCI (205 mg, 86%).
Data of Ex.244.HCI: C26H30FN306S.HCI (519.6, free base). LC-MS (method 1d): Pt =
1.55 (92), 520.0 ([M+H]). 11-I-NMR (DMSO-d6): 8.48 (s, 1 H); 8.40 -8.25 (br.
s, 4 H);
8.05 (d, J = 7.9, 1 H); 7.86 (s, 1 H); 7.31 (d, J = 8.8, 1 H); 6.73 (d, J =
10.6, 1 H); 4.72 - 4.61 (m, 2 H); ca 4.4 - 4.3 (br. m, 2 H); 4.00 - 3.68 (m, 5 H); 3.68 (s, 3 H); 3.49 -3.43 (m, not resolved, 2 H), ca 2.5 (m, superimposed by DMSO-d signal, 1 H);
2.40 -2.25 (m, 2 H), 2.02 (m, 1 H); 1.79 - 1.52 (m, 4 H).
Core 15: Synthesis of selected advanced intermediates and final products (Scheme 18) Synthesis of Ex.246 At 0 C, i-Pr2NEt (0.054 mL, 0.32 mmol) was added to a soln of Ex.243 (ca. 70%
w/w;
55 mg, 0.064 mmol), HATU (36 mg, 0.095 mmol), HOAt (13 mg, 0.095 mmol) and aniline (0.029 mL, 0.32 mmol) in CH2Cl2 (1.5 mL) and DMF (0.5 mL). The mixture was stirred for 30 min followed by an aqueous workup (CH2Cl2, 1 M aq. HCI
soln, sat.

aq. NaHCO3 soln, sat. aq. NaCI soln; Na2SO4) and FC (hexane/Et0Ac 2:1 to 1.1) to afford Ex.246 (27 mg, 62%).
Data of Ex.246: cf. Table 27b Synthesis of Ex.247 At 0 C, 4 M HCI in dioxane (0.20 mL) was added to a soln of Ex.246 (25 mg, 0.037 mmol) in dioxane (0.6 mL). The mixture was stirred for 5 h at 0 C to rt. More in dioxane (0.15 mL) was added and the mixture was stirred at rt for 16 h. The volatiles were evaporated. The residue was treated with TFA (0.15 mL) in CH2Cl2 (0.75 mL) for 1 h at 0 C, followed by evaporation of the solvents, aqueous workup (Et0Ac, sat.aq. Na2CO3 soln; Na2SO4) and FC (CH2C12/Me0H 100:0 to 90:10). The purified product (13 mg) was dissolved in dioxane (0.3 mL) and treated with 4 M HCI
in dioxane (0.05 mL). The volatiles were evaporated to give Ex.247.HCI (14 mg, 60%).
Data of Ex.247-HCI: cf. Table 27b 1H-NMR (DMSO-d6): 10.18 (s, 1 H); 8.48 (s, 1 H); 8.30 (s, 1 H); 8.15 (d, J =
7.1, 1 H);
8.15 (br. s, 3 H); 7.85 (s, 1 H); 7.59 (d, J = 7.7, 2 H); 7.36 -7.27 (m, 3 H);
7.06 (t, J =
7.4, 1 H); 6.74 (dt-like m, 1 H); 4.73 - 4.63 (m, 2 H); 4.40 (br. not resolved m, 1 H);
4.01 - 3.59 (m, 5 H); 3.50 - 3.41 (m, 3 H); 2.36 (br. t-like m, 2 H); 2.04 (m, 1 H); 1.90 - 1.45 (several not resolved m, 5 H).
Synthesis of Ex.256 Ex.256 (8 mg, 14%) was obtained from Ex.243 (ca. 70% w/w; 65 mg, 0.075 mmol) and 4-chloroaniline (48 mg, 0.38 mmol) by applying the method described for the synthesis of Ex.246.
Data of Ex.256: cf. Table 27b Synthesis of Ex.257 Ex.257-HCI (4 mg, 66%) was obtained from Ex.256 (7 mg, 0.01 mmol) by applying the method described for the synthesis of Ex.247.HCI.
Data of Ex.257.HCI: cf. Table 27b Synthesis of Ex.258 Ex.258 (19 mg, 43%) was obtained from Ex.243 (ca. 70% w/w; 55 mg, 0.064 mmol) and m-toluidine (0.034 mL, 0.32 mmol) by applying the method described for the synthesis of Ex.246.

Data of Ex.258: cf. Table 27b Synthesis of Ex.259 Ex.259-11C1 (10 mg, 66%) was obtained from Ex.258 (17 mg, 0.024 mmol) by applying the method described for the synthesis of Ex.247-FICI.
Data of Ex.259-HCI: cf. Table 27b 1H-NMR (DMSO-d6): 10.07 (s, 1 H); 8.47 (s, 1 H); 8.30 (s, 1 H); 8.12 (d, J =
7.6, 1 H);
8.12 (br. s, 3 H); 7.85 (s, 1 H); 7.42 -7.30 (m, 3 H), 7.18 (t, J = 7.4, 1 H);
6.88 (d, J ca 7.6, 1 H); 6.74 (d, J = 10.3, 1 H); 4.78 -4.60 (m, 2 H); 4.40 (br. not resolved m, 1 H);
4.05 -3.65 (m, 5 H); 3.51 -3.40 (m, 3 H); 2.37 (br. t-like m, 2 H); 2.27 (s, 3 H); 2.01 (m, 1 H); 1.90 - 1.45 (several not resolved m, 5 H).
Core 16: Synthesis of Ex.262, Ex.263 and Ex.264 (Scheme 19) Synthesis of the Mitsunobu product 154 CMBP (8.5 mL, 32 mmol) was added to a soln of hydroxythiophene 106 (5.69 g, 20 mmol) and alcohol 118 (9.8 g, 26 mmol) in toluene (77 mL). The mixture was heated to reflux for 2 h and concentrated. FC (hexane/Et0Ac 90:10 to 20:80) gave 154 (12.68 g, 98%).
Data of 154: C29H34BrN306S (632.6). LC-MS (method 4a): R = 2.29 (93), 634.3/632.3 ([M+H]).
Synthesis of the amino acid 157 A soln of 154 (12.6 g, 20 mmol) in CH2Cl2 (128 mL) was treated with TFA (148 mL) and heated to reflux for 3 h. The volatiles were evaporated. The residue was suspended in toluene, concentrated and dried i.v. to give crude 155 (16.15 g, containing residual solvent), which was used without further purification.
At 0 C, i-Pr2NEt (6.85 mL, 40.3 mmol) was added to a soln of crude carboxylic acid 155 (9.27 g, ca 11.5 mmol), amine 130-HCI (5.52 g, 16.1 mmol), HATU (7.66 g, 20.1 mmol) and HOAt (2.74 g, 20.1 mmol) in DMF (170 mL). The mixture was stirred at it for 2 h, followed by an aqueous workup (Et0Ac, 1 M aq. HCI soln, sat. aq.
NaHCO3 soln; Na2SO4) and FC (CH2C12/Me0H 100:0 to 95:5) to afford 156 (11.7 g;
containing residual DMF), used without further purification.
A degassed solution of 156 (11.6 g) and 1,3-dimethylbarbituric acid (6.3 g, 40 mmol) in CH2Cl2 (39 mL) and Et0Ac (78 mL) was treated with Pd(PPh3)4 (1.6 g, 1.3 mmol) at rt for 4 h. The volatiles were evaporated. FC (Et0Ac, then CH2C12/Me0H
100:0 to 80:20) afforded 157 (7.6 g, 89% over the three steps).
Data of 157: C341-138BrN607S (740.6). LC-MS (method 1a): R1 = 1.91 (87), 740.1/742.1 P11+119.
Synthesis of Ex.262 A soln of 157 (1.9 g, 2.57 mmol) in CH2Cl2 (40 mL) was added dropwise over 2 h (syringe pump) to a soln of T3P (50% in Et0Ac, 7.56 mL, 12.8 mmol) and i-Pr2NEt (1.96 mL, 11.5 mmol) in CH2Cl2 (1190 mL). Stirring at rt was continued for 4 h. The volatiles were evaporated. Aqueous workup (CH2Cl2, sat. aq. NaHCO3 soln.;
Na2SO4) and FC (hexane/Et0Ac 50:50 to 0:100) afforded Ex.262 (1.63 g, 88%).
Data of Ex.262: C34F136BrN606S (722.6). LC-MS (method 1d): R1 = 2.52 (99), 722.0/724.0 ([M+H]). 1H-NMR (DMSO-d6): 7.65 (d, J = 6.8, 1 H); 7.49 (d, J =
8.0, 2 H); 7.41 -7.26 (m, 8 H); 7.08 (d, J = 5.4, 1 H); 6.64 (s, 1 H); 5.06 (s, 2 H);
ca 4.5 -4.4 (br. m, 2 H); 4.48 (s, 2 H); 4.32 (br. d, J ca 8.8, 1 H); 4.16 (br. m, 2 H); 4.01 (m, 1 H); 3.86 (s, 3 H); 3.69 (br. m, 1 H); 3.46- 3.32 (m, 2 H); 2.96 (s, 3 H); 2.40 - 2.25 (br.
m, 2 H), 2.10 - 1.90 (br. m, 2 H).
Synthesis of Ex.263 At 0 C, BCI3 (16 mL, 16 mmol) was added dropwise to a soln of Ex.262 (2.34 g, 3.2 mmol) in CH2Cl2 (83 mL). The mixture was allowed to stir at 0 C to rt for 16 h. The mixture was cooled to 0 C and poured slowly into Me0H. The mixture was concentrated. Aqueous workup (CH2Cl2, sat. aq. NaHCO3 soln; Na2SO4) afforded Ex.263 (1.21 g, 89%).
Data of Ex.263: C19H26N604S (419.5). LC-MS (method 1d): R = 1.11 (98), 420.0 ([M+Hy). 1H-NMR (DMSO-d6): 7.40 (d, J = 5.5, 1 H); 7.08 (d, J = 5.5, 1 H);
6.63 (s, 1 H); 5.17 (d, J = 5.1, 1 H); 4.35 -4.29 (m, 2 H); 4.24 (dd, J = 6.6, 11.9, 1 H); 4.12 -3.97 (m, 3 H); 3.85 (s, 3 H); 3.68 (d, J = 7.4, 1 H); 3.61 (m, 1 H); 3.17 (dd, J = 6.6, 10.2, 1 H); 2.97 (s, 3 H); 2.28 -2.19 (m, 2 H); 1.95 (m, 1 H), 1.90 - 1.75 (br. not resolved m, 3 H).
Synthesis of Ex.264 At rt, TBAF (1 M in THF; 0.119 mL, 0.119 mmol) was slowly added to a soln of Ex.262 (160 mg, 0.221 mmol) in THF (2.5 mL). The mixture was heated to reflux for 2 h, filtered through a pad of celite and concentrated. Aqueous workup (CH2Cl2, sat. aq.

NaHCO3 soln; Na2SO4) and FC (CH2C12/Me0H 85:15) afforded a white solid (100 mg) was dissolved in DMF (4.0 mL) and hydrogenated for 2 h at rt and normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50%
H20;
23 mg). The volatiles were evaporated. The crude product was purified by FC
(CH2C12/Me0H 100:0 to 80:20) to give Ex.264 (45 mg, 40%).
Data of Ex.264: C26H31N504S (509.6). LC-MS (method la): Rt = 1.62 (99), 510.1 ([M+H]+). 1H-NMR (DMSO-d6): 7.40 (d, J = 5.5, 1 H); 7.33 - 7.27 (m, 5 H); 7.08 (d, J =
5.5, 1 H); 6.65 (s, 1 H); 4.53 (s, 2 H); 4.41 -4.17 (m, 5 H); 3.98 (dd, J =
5.1, 9.4, 1 H);
3.85 (s, 3 H); 3.72 (d, J = 7.0, 1 H); 3.61 (m, 1 H); ca 3.3 (m, superimposed by H20 signal, 1 H); 2.97 (s, 3 H); 2.40- 1.80 (several br. m, 6 H).
Core 16: Synthesis of selected advanced intermediates and final products (Scheme 19) Synthesis of Ex.265 At 0 C, oxalyl chloride (0.104 mL, 1.19 mmol) and one drop of DMF were added to a soln of 2-naphthaleneacetic acid (53 mg, 0.29 mmol) in CH2Cl2 (6 mL). The mixture was stirred at it for 1 h and concentrated. The residue was dissolved in CH2Cl2 (2.5 mL) and added dropwise to a soln of Ex.263 (100 mg, 0.24 mmol) and i-Pr2NEt (0.204 mL, 1.19 mmol) in CH2Cl2 (3.5 mL). The mixture was stirred at 0 C for 1 h followed by an aqueous workup (CH2Cl2, sat. aq. NaHCO3 soln; Na2SO4) and FC
(CH2C12/i-PrOH 100:0 to 95:5) to yield Ex.265 (110 mg, 78%).
Data of Ex.265.: cf. Table 28b 1H-NMR (DMSO-d6): 8.54 (d, J = 7.5, 1 H); 7.89 - 7.85 (m, 3 H); 7.78 (s, 1 H);
7.52 -7.44 (m, 3 H); 7.40 (d, J = 5.5, 1 H); 7.09 (d, J = 5.5, 1 H); 6.44 (s, 1 H);
5.14 (d, J =
4.9, 1 H); 4.65 (br. t, J = 8.0, 1 H); 4.40 -4.31 (m, 2 H); 4.11 (q, J ca 5.8, 1 H); 4.03 (m, 1 H), 3.84 (m, 1 H); 3.84 (s, 3 H); 3.68 (s, 2 H); 3.64 (m, 1 H); ca 3.30 (m, 1 H, partially superimposed by H20 signal); 3.17 (dd, J = 6.3, 10.5, 1 H); 2.91 (s, 3 H);
2.35 (m, 1 H); 2.18 (m, 1 H); 1.91 -1.82 (m, 2 H).
Synthesis of Ex.275 Trimethyloxonium tetrafluoroborate (15 mg, 0.10 mmol) was added at 0 C to a solution of Ex.265 (40 mg, 0.068 mmol) and N,N,N',N'-tetramethy1-1,8-naphthalenediamine (22 mg, 0.102 mmol) in CH2Cl2 (1.0 mL). The mixture was stirred at 0 C to it for 4.5 h. More N,N,N',N'-tetramethy1-1,8-naphthalenediamine (32 mg, 0.15 mmol) and trimethyloxonium tetrafluoroborate (22 mg, 0.15 mmol) were added at 0 C and stirring was continued at it for 16 h. Aqueous workup (CH2Cl2, 2 M

aq. HCI soln; Na2SO4). The residue was suspended in CH2Cl2 and filtered. The filtrate was purifie by FC (Et0Ac/Me0H 100:0 to 97:3) and by prep. RP-HPLC (method la) to afford Ex.275 (5 mg, 12%).
Data of Ex.275-: cf. Table 28b 1H-NMR (DMSO-d6): 8.57 (d, J = 7.5, 1 H); 7.90 - 7.85 (m, 3 H); 7.80 (s, 1 H);
7.54 -7.45 (m, 3 H); 7.39 (d, J = 5.5, 1 H); 7.07 (d, J = 5.5, 1 H); 6.62 (s, 1 H);
4.65 (br. t, J
= 7.8, 1 H); 4.40 (br. not resolved m, 1 H); 4.29 (dd; J = 2.7, 9.5, 1 H);
3.96 -3.83 (m, 2 H); 3.83 (s, 3 H); 3.75 - 3.60 (m, 2 H); 3.67 (s, 2 H); ca 3.3 - 3.2 (m, 2 H, partially superimposed by H20 signal); 3.05 (s, 3 H); 2.92 (s, 3 H); 2.36 (m, 1 H); 2.16 (m, 1 H); 1.96 - 1.83 (m, 2 H).
Synthesis of Ex.276 At 0 C, i-Pr2NEt (0.061 mL, 0.36 mmol) and 2-naphthylisocyanate (22 mg, 0.131 mmol) were added to a soln of Ex.263 (50 mg, 0.12 mmol) in CH2Cl2 (1.0 mL).
The mixture was stirred at 0 C to rt for 60 min. Aqueous workup (CHCI3, sat. aq.
Na2CO3 soln; Na2SO4) and purification by prep. HPLC (method 3) afforded Ex.276 (50 mg, 71%).
Data of Ex.276-: cf. Table 28b 1H-NMR (DMSO-d6): 9.00 (s, 1 H) 8.05 (d, J = 1.8, 1 H); 7.81 - 7.74 (m, 3 H);
7.45 -7.40 (m, 3 H); 7.32 (dt, J = 1.2, 7.5, 1 H); 7.11 (d, J = 5.5, 1 H); 6.74 (d, J = 7.3, 1 H);
6.68 (s, 1 H); 5.24 (d, J = 5.0, 1 H); 4.77 (br. t, J = 7.1, 1 H); 4.38 -4.32 (m, 2 H);
4.29 (q-like m, 1 H); 4.07 - 4.00 (m, 2 H), 3.88 (s, 3 H); 3.85 (m, 1H); ca 3.30 - 3.20 (m, 2 H, partially superimposed by H20 signal); 2.98 (s, 3 H); ca 2.5 (m, 1 H, superimposed by DMSO-d signal); 2.27 (m, 1 H); 2.00 - 1.92 (m, 2 H).
Core 17: Synthesis of Ex.284a, Ex.285 and Ex.286 (Scheme 20) Synthesis of amide 158 A suspension of 110=HCI (6.2 g, 19.9 mmol) in CH2Cl2 (310 mL) was cooled to 0 C.
Oxalyl chloride (5.1 mL, 59.7 mmol) was added followed by DMF (0.37 mL). The mixture was stirred for 1.5 h at rt and concentrated. The residue was suspended in CH2Cl2 and concentrated; this operation was repeated once and the residue was then dried i.v. The residue was suspended in CH2Cl2(180 mL). A soln of 131 -NCI
(8.86 g, 23.9 mmol) in CH2Cl2 (120 mL) was added. The mixture was cooled to 0 C
followed by the slow addn of i-Pr2NEt (17.0 mL, 99.5 mmol). The mixture was stirred for 1 h at 0 C. Aqueous workup (CH2Cl2, 1 M aq. HCI soln, sat. aq. NaHCO3 soln; Na2SO4) and FC (hexane/Et0Ac gradient) gave 158 (8.1 g, 69%).
Data of 158: C301-133N508 (591.6). LC-MS (method la): R = 2.43 (94), 592.1 ([M+H]).
Synthesis of the Mitsunobu product 159 A soln of of CMBP (6.58 g, 27.3 mmol) in toluene (30 mL) was added to a soln of phenol 158 (8.07 g, 13.6 mmol) and alcohol 120 (3.28 g, 17.7 mmol) in toluene (131 mL). The mixture was heated to reflux for 1 h and concentrated. FC
(hexane/Et0Ac 50:50 to 0:100) yielded 159 (7.9 g, 76%).
Data of 159: C391-146N6010 (758.8). LC-MS (method 4a): Rt = 1.91 (90), 759.2 ([M+H]).
Synthesis of the amino acid 160 A degassed solution of 159 (8.9 g, 11.8 mmol) and 1,3-dimethylbarbituric acid (4.4 g, 28,3 mmol) in CH2Cl2 (180 mL) and Et0Ac (45 mL) was treated with Pd(PPh3)4 (1.36 g, 1.18 mmol) at rt for 2 h. The volatiles were evaporated. FC (Et0Ac, then CH2C12/Me0H 100:0 to 40:60) afforded 160 (7.33 g, 98%; containing some impurities;
used without further purification).
Data of 160: C32H38N608 (634.7). LC-MS (method 1a): Rt = 1.65 (88), 635.2 ([M+H]+).
Synthesis of Ex.284a and Ex.284b A soln of 160 (500 mg, 0.79 mmol) in pyridine (40 mL) was added dropwise over 2 h (syringe pump) to a soln of HATU (900 mg, 2.36 mmol) and HOAt (322 mg, 2.36 mmol) in pyridine (1500 mL). An additional portion of HATU (900 mg, 2.36 mmol) and HOAt (322 mg, 2.36 mmol) was added to the solution. Again a soln of 160 (500 mg, 0.79 mmol) in pyridine (40 mL) was added dropwise over 2 h (syringe pump).
The volatiles were evaporated. Aqueous workup (CH2Cl2, sat. aq. NaHCO3 soln, H20, Na2SO4). Purification by preparative HPLC (method 1d) afforded Ex.284a.CF3CO2H

(480 mg) and Ex.284b-CF3CO2H (186 mg, 16%).
Ex.284a-CF3CO2H (480 mg) was dissolved in CH2Cl2 and washed with sat. aq.
NaHCO3 soln. The organic phase was dried (Na2SO4), filtered and concentrated to afford Ex.284a (442 mg, 45%).
Data of Ex.284a: C32H361\1607 (616.6). LC-MS (method 1d): Rt = 2.24 (99), 617.2 ([M+H]+). 1H-NMR (DMSO-d6): 8.66 (d, J = 2.1, 1 H); 8.40 (dd, J = 2.1, 8.9, 1 H); 7.53 - 7.49 (m, 2 H); 7.36 - 7.26 (m, 6 H); 5.06 (br. d, J = 12.6, 1 H); 4.92 (s, 2 H); 4.37 (br. dd, J ca 2.6, 13.0, 1 H); 4.15 (t-like m, 1 H); 3.65 (br. t, J ca 8.7, 1 H); 3.55 (q-like m, 1 H); 3.27 (m, 1 H); 3.01 (s, 3 H); 2.95 -2.82 (m, 2 H), 2.61 (s, 3 H);
1.97 - 1.68 (several m, 6 H),1.23 - 0.90 (br. m, 4 H).
Data of Ex.284b=CF3CO2H: C32H36N607.CF3CO2H (free base 616.6). LC-MS (method d): Rt = 2.14 (99), 617.2 ([M+H]).
Synthesis of Ex.285 A soln of Ex.284a (380 mg, 0.62 mmol) in THF (19 mL) was treated with TBAF (1 M
in THF; 0.6 mL, 0.6 mmol) at 75 C for 7 h. The mixture was cooled to rt and TBAF (1 M in THF; 0.3 mL, 0.3 mmol) was added. Stirring at 75 C was continued for 8 h.
The volatiles were evaporated. FC (CH2C12/Me0H 95:5 to 90:10) afforded Ex.285 (182 mg, ca 60%; containing ca 5% of tetrabutylammonium salts). An analytical sample (15 mg) was further purified by preparative HPLC (method 2a) to afford Ex.285 (9 mg).
Data of Ex.285: C24H30N605 (482.5). LC-MS (method 1d): Rt = 1.47 (95), 483.2 ([M+Hp-). 1H-NMR (DMSO-d6): 8.66 (d, J = 2.2, 1 H); 8.41 (dd, J = 2.2, 9.0, 1 H); 7.51 (s, 1 H); 7.47 (d, J = 9.1, 1 H); 5.17 (d, J = 12.5, 1 H); 4.30 (dd, J = 2.3, 12.7, 1 H);
4.14 (t, J = 7.0, 1 H); 3.51 (m, 1 H); ca. 3.2 (m, 1 H), 3.02 (s, 3 H); 2.97 (m, I H); 2.81 -2.68 (m, 2 H); 2.61 (s, 3 H); 2.0 - 1.7 (several m, 8 H); 1.4 - 0.6 (several m, 4 H).
Synthesis of Ex.286 A soln. of Ex.284a (1.2 g, 1.95 mmol) in Me0H (120 mL) was hydrogenated in the presence of platinum (IV) oxide hydrate (120 mg) for 8 h at rt and normal pressure.
More platinum (IV) oxide hydrate (60 mg) was added and the hydrogenation was continued for 6 h. The mixture was filtered through a pad of celite. The solid was washed (Me0H). The combined filtrate and washings were concentrated. FC
(hexane/Et0Ac 50:50:0 to 0:100 then CH2C12/Me0H 90:10) yielded Ex.286 (0.75 g, 66%).
Data of Ex.286: C32H38N606 (586.7). LC-MS (method 1d): Rt = 1.68 (90), 587.2 ([M+H]f). 1H-NMR (DMSO-d6): 7.67 (d, J = 2.0, 1 H); 7.48 -7.43 (m, 2 H); 7.39 -7.27 (m, 6 H); 6.87 (d, J = 8.6, 1 H); 5.06 -4.93 (m, 5 H); 4.11 (br. m, not resolved, 1 H);
4.00 (br. d, J ca 11.7, 1 H); 3.60 (br. t, J ca. 8.4, 1 H); 3.49 (q-like m, 1 H); 3.15 (m, 1 H), 2.99 (s, 3 H); 2.96 (m, 1 H); 2.78 (m, 1 H); 2.54 (s, 3 H); 2.21 (m, 1 H);
2.15 - 1.15 (several br. m, 8 H); 0.66 (br. m, 1 H).

Core 18: Synthesis of Ex.305 and Ex.306 (Scheme 21) Synthesis of the Mitsunobu product 161 DEAD (40% in toluene; 11.1 mL, 24.3 mmol) was slowly added to a soln of alcohol 122 (5.66 g, 16.2 mmol), 2-iodophenol (111; 5.33 g, 24.3 mmol) and PPh3 (6.36 g, 24.3 mmol) in toluene (345 mL). The mixture was stirred at rt for 4 h. The volatiles were evaporated. FC (hexane/Et0Ac gradient) afforded 161 (6.85 g, 77%).
Data of 161: C24H29IN205 (552.4). LC-MS (method la): Rt = 2.71 (99), 553.2 ([M+H]+).
1H-NMR (DMS0-1:16): 7.76 (d, J = 7.7, 1 H); 7.60 (d, J = 6.5, 1 H); 7.40 -7.28 (m, 6 H); 7.02 (d, J = 8.2, 1 H); 6.76 (t, J = 7.5, 1 H); 5.03 (s, 2 H); 4.33 (br.
m, 1 H); 4.17 -4.07 (br. m, 3 H); 3.59 (br. m, 1 H); 3.29 (br. m, 1 H); 2.26 (br. m, 1 H);
2.02 (br. m, 1 H); 1.38 (s, 9 H).
Synthesis of the biphenyl 162 Pd(dppf)Cl2CH2C12 (1.0 g, 1.2 mmol) was added to a mixture of 161 (6.8 g, 12.3 mmol), ethyl 2-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)benzoate (113; 3.0 g, 10.8 mmol), 2-(ethoxycarbonyl)phenylboronic acid (112; 2.3 g, 11.8 mmol) in DME
(325 mL), Et0H (32 mL) and 1 M aq. Na2CO3 soln (37 mL). The mixture was heated to 80 C for 3 h. The mixture was diluted with sat. aq. NaHCO3 soln and repeatedly extracted with CH2Cl2. The combined organic layer was dried (Na2SO4), filtered and concentrated. FC (hexane/Et0Ac gradient) gave 162 (6.6 g, 94%).
Data of 162: C33H38N207 (574.6). LC-MS (method 4c): Rt = 2.48 (96), 575.4 ([M+H]').
IH-NMR (DMSO-d6): 7.80 (d, J = 7.5, 1 H); 7.58 (t, J = 7.3, 1 H); 7.46 - 7.25 (m, 9 H);
7.12 (m, 1 H); 7.03 - 7.00 (m, 2 H); 4.99 (s, 2 H); 3.99 - 3.83 (br. m, 6 H);
3.78 (br.
not resolved m, 1 H); 3.01 (br. not resolved m, 1 H); 1.81 (br. not resolved m, 1 H);
1.72 (br. not resolved m, 1 H); 1.33 (s, 9 H); 0.88 (br. t, 3 H).
Synthesis of the carboxylic acid 164 A soln of 162 (5.2 g, 9.1 mmol) in Et0H (50 mL) was hydrogenated for 3 h at rt and normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50% H20; 0.5 g). The mixture was filtered through a pad of celite.
The residue was washed with Et0H. The combined filtrate and washings were concentrated to give crude 163 (4.0 g) which was dissolved in Et0H (84 mL).
KOH
(10.2 g, 182 mmol) dissolved in H20 (28 mL) was added and the mixture was stirred at 45 C for 18 h. The solution was cooled to it. NaHCO3 (15.2 g, 182 mmol) and CH2Cl2 (100 mL) followed by Cbz0Su (2.7 g, 10.8 mmol) were successively added and the mixture was allowed to stir for 3 h. The mixture was acidified by addn of 3 M

aq. HCI soln and extracted with CH2Cl2. The organic layer was dried (Na2SO4), filtered and concentrated. FC (Et0Ac) afforded 164 (4.87 g, 98%) Data of 164: C31H341\1207(546.6). LC-MS (method 1c): Rt = 2.44 (88), 547.1 ([M+H].).
Synthesis of the amide 165 EDC.HCI (3.4 g, 17.8 mmol) was added to a soln of 164 (4.8 g, 8.9 mmol) and sarcosine tert.-butylester hydrochloride (132; 3.2 g, 17.8 mmol) in pyridine (150 mL).
The mixture was stirred at rt for 3 h. Aqueous workup (CH2Cl2, aq. 2 M HCI
soln, sat.
aq. NaHCO3 soln; Na2SO4) and FC (hexane/Et0Ac gradient) afforded 165 (4.9 g, 82%).
Data of 165: C391-147N308(673.8). LC-MS (method 1a): R = 2.71 (97), 674.2 (WH-Hr).
Synthesis of Ex.305 A soln of 165 (4.9 g, 7.3 mmol) in CH2Cl2 (50 mL) was treated with TFA (25 mL) for 4 h at rt. Evaporation of the volatiles afforded the crude amino acid 166-CF3CO2H (5.3 g, containing residual solvent) which was used without further purification.
The ring closing reaction was performed in four batches:
A soln of crude 166-CF3CO2H (1.3 g) and i-Pr2NEt (1.5 mL, 8.7 mmol) in CH2Cl2 (40 mL) was added dropwise over 2 h (syringe pump) to a soln of T3P (50% in Et0Ac, 2.2 mL, 3.7 mmol) in CH2Cl2 (1200 mL). The mixture was stirred for 1 h at rt and concentrated.
The four batches were combined and purified by FC (hexane/Et0Ac/Me0H gradient) to give Ex.305 (3.7 g, quant. yield).
Data of Ex.305: C29H29N305 (499.5). LC-MS (method 1a): Rt = 2.00 (98), 500.1 ([M+H]+). 1H-NMR (CD300): Two sets of signals were observed; ratio 7:3; 7.48 -7.21 (m, 11 H), 7.12 - 6.96 (m, 1.3 H); 6.91 (t, J = 7.5, 0.7 H); 5.10 - 5.04 (m, 2 H); 4.72 (dd, J = 4.2, 9.7, 0.7 H); 4.40 -4.28 (m, 1.3 H); 4.16 - 4.06 (m, 1.6 H); 4.03 (dt, J =
4.0, 7.8, 0.7 H); 3.93 (br. not resolved m, 0.7 H); 3.78 (d, J = 14.6, 0.3 H);
3.69 (br. d, 0.7 H); 3.59 -3.50 (m, 1.3 H); 3.10, 3.07 (2 s, 3 H); 2.99 (br. d, J ca 10.0, 0.7 H); 2.10 - 1.93 (m, 2 H).
Synthesis of Ex.306 A soln of Ex.305 (3.68 g, 7.3 mmol) in Me0H (50 mL) was hydrogenated for 4 h at rt and normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50% H20; 0.38 g). The mixture was filtered through a pad of celite.

The residue was washed (Me0H). The combined filtrate and washings were concentrated. FC (hexane/Et0Ac/Me0H gradient) afforded Ex.306 (2.4 g, 89%).
Data of Ex.306: C21H23N303 (365.4). LC-MS (method 1a): Rt = 1.17 (96), 366.0 ([M+H]+).
Core 19: Synthesis of Ex.327, Ex.328 and Ex.329 (Scheme 22) Synthesis of the amide 167 At 0 C, i-Pr2NEt (4.5 mL, 26.3 mmol) was added dropwise to a soln of 117 (1.2 g, 4.4 mmol), 125=HCI (1.73 g, 5.2 mmol), HATU (1.67 g, 4.4 mmol) and HOAt (0.60 g, 4.4 mmol) in DMF ( 30 mL) and THF (45 mL). The mixture was stirred at rt for 1.5 h.
Aqueous workup (Et0Ac, 0.1 M aq. HCI soln, sat. aq. NaCI soln; Na2SO4) and FC
(hexane/Et0Ac 2:1 to 1:1) afforded 167 (1.24 9,51%).
Data of 167: C26H24F3N307 (547.5). LC-MS (method 1c): Rt = 2.37 (89), 548.2 ([M+H].).
Synthesis of the Mitsunobu product 168 A soln of phenol 167 (1.23 g, 2.2 mmol), alcohol 16 ( 0.81 g, 2.7 mmol) and CMBP
(1.36 g, 5.6 mmol) in toluene (30 mL) was heated to reflux for 1.5 h.
Evaporation of the volatiles and FC (CH2C12/Et0Ac 3:1 to 1:1) afforded 168 (1.84 g, 99%).
Data of 168: C40H46F3N5011 (829.8). LC-MS (method 4a): R = 2.00 (92), 830.4 ([M+ H]).
Synthesis of the amino acid 169 A degassed solution of 168 (1.8 g, 2.2 mmol) and 1,3-dimethylbarbituric acid (0.89, 5.3 mmol) in CH2Cl2 (15 mL) and Et0Ac (15 mL) was treated with Pd(PPh3)4 (0.13 g, 0.1 mmol) at rt for 1 h. The volatiles were evaporated. FC (CH2C12/Me0H 99:1 to 80:20) afforded 169 (1.329, 85%).
Data of 169: C33H38F3N509 (705.7). LC-MS (method 1a): R = 1.95 (94), 706.3 ([M+1-1]+).
Synthesis of Ex.327 A mixture of 169 (1.33 g, 1.9 mmol), i-Pr2NEt (1.6 mL, 9.4 mmol) and CH2Cl2 (40 mL) was slowly added over 2 h (syringe pump) to a soln of T3P (50% in Et0Ac; 3.3 mL, 5.6 mmol) and i-Pr2NEt (1.6 mL, 9.4 mmol) in CH2Cl2 (1880 mL). The volatiles were partially evaporated. The soln was washed (sat. aq. NaHCO3 soln), dried (Na2SO4), filtered and concentrated. FC (hexane/Et0Ac 25:75 to 0:100) afforded Ex.327 (0.96 g, 74%).
Data of Ex.327: C33H36F3N508 (687.6). LC-MS (method 1f): R1 = 2.43 (89), 688.3 ([M+Hr). 1H-NMR (DMSO-d6): Three sets of signals were observed; ratio 2:1:1;
9.16 (br. s, 0.5 H); 8.65 (br. s, 0.25 H); 8.50 (br. s, 0.25 H); 7.56 - 7.08 (m, 10 H); 5.13 -4.92 (several d, 2 H); 4.40 -2.98 (several br. not resolved m, 12 H); 2.43 -2.04 (br.
not resolved m, 1 H); 1.95 - 1.70 (br. not resolved m, 1 H); 1.41, 1.39 (2 s, 9 H).
Synthesis of Ex.328 A soln of Ex.327 (60 mg, 0.087 mmol) in EtOAc (5 mL) was hydrogenated for 3 h at rt and normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50% H20; 30 mg). The mixture was filtered through a pad of celite.
The residue was washed (Et0Ac). The combined filtrate and washings were concentrated. FC (CH2C12/Me0H 95:5 to 90:10) afforded Ex.328 (37 mg, 77%).
Data of Ex.328: C25H30F3N506 (553.5). LC-MS (method 1d): R = 1.84 (96), 554.2 ([M+H]+). 1H-NMR (DMSO-d6): Two sets of signals were observed; ratio 4:6; 9.19 (t-like m, 0.4 H), 8.72 (Nike m, 0.6 H); 7.57 (not resolved m, 1 H); 7.48 - 7.30 (m, 2 H);
7.23 (d, J = 5.1, 1 H); 7.04 (not resolved m, 1 H); 4.50 -4.34 (2 m, 1 H);
4.20 -4.13 (m, 2 H); 4.07 - 3.94 (m, 2 H); 3.84 - 3.30 (several m, 3 H); 3.19 -2.66 (several m, 5 H); 2.42, 2.26 (2 m, 1 H); 1.95, 1.70 (2 m, 1 H); 1.40 (s, 9 H).
Synthesis of Ex.329 Ex.327 (50 mg, 0.073 mmol) was dissolved in CH2Cl2 (2 mL). At 0 C, TFA (0.03 mL, 0.36 mmol) was added and the soln was stirred for 1.5 h. Aqueous workup (Et0Ac, sat. aq. NaHCO3 soln, sat aq. NaCI soln; Na2SO4) and treatment of the product with HCI in dioxane afforded Ex.329.HCI (33 mg, 73%).
Data of Ex.329-HCI: C28H28F3N506.HCI (free base; 587.5). LC-MS (method 1d): Rt =
1.69 (97), 588.2 ([M+Hr).

General Procedures Attachment of substituents to the macrocyclic core structures:
Synthesis of the final products Acylation, carbamoylation, sulfonylation, and alkylation reactions Procedure A
A.1.: Amide coupling of a macrocyclic amine with A.1.1: Carboxylic acid and HATU
A soln of an amino macrocycle (free amine or hydrochloride; 0.085 mmol), a carboxylic acid (1.2 equiv.), HATU (1.5 equiv.) and HOAt (1.5 equiv.) in DMF
(0.5 mL) was treated at rt with i-Pr2NEt (3.0 equiv.). The mixture was stirred at rt for 2 - 15 h.
The mixture was distributed between CH2Cl2 and 1 M aq. HCI soln. The organic phase was washed (sat. aq. NaCI soln), dried (Na2SO4), filtered and concentrated.
Purification of the crude product by chromatography (FC, normal phase or reversed phase prep. HPLC) afforded a macrocyclic N-acyl amine.
A.1.2: Acyl chloride or carboxylic acid anhydride At 0 C, a soln of an amino macrocycle (free amine or hydrochloride; 0.085 mmol) in CH2Cl2 (0.5 mL) was successively treated with pyridine (5 equiv.) and carboxylic acid chloride (1.05 ¨ 2 equiv.) or carboxylic acid anhydride (1.05 ¨ 2 equiv.). The mixture was stirred at 0 C to rt for 2 - 15 h. After the addn of Me0H (0.01 mL) the soln was stirred for 10 min and concentrated. Toluene was added to the crude product and evaporated. Purification of the residue by chromatography (FC, normal phase or reversed phase prep. HPLC) afforded a macrocyclic N-acyl amine.
A.1.2.1: Acyl chloride Like A.1.2 and after 15 h at rt more carboxylic acid chloride (2 equiv.) and i-Pr2NEt (3 equiv.) were added. Stirring was continued for 24 h followed by an aq. workup (CHCI3, sat. aq. Na2003 soln; Na2SO4).
A.1.2.2: Acyl chloride At 0 C, a soln of an amino macrocycle (free amine or hydrochloride; 1 mmol) in CH2Cl2 (7 mL) was successively treated with i-Pr2NEt (5 equiv.) and carboxylic acid chloride (1.05 ¨ 2 equiv.). The mixture was stirred at 0 C to rt for 2 - 15 h.
Aq. workup (CHCI3, sat. aq. Na2CO3 soln; Na2SO4). Purification of the crude product by chromatography (FC, normal phase or reversed phase prep. HPLC) afforded a macrocyclic N-acyl amine.
A.1.3: Carboxylic acid and T3P

A soln of a carboxylic acid (2.4 equiv.), T3P (50% in DMF; 3 equiv.) and i-Pr2NEt (4.0 equiv.) in DMF (0.3 mL) was slowly added to a mixture of an amino macrocycle (free amine or hydrochloride; 0.1 mmol) and DMF (0.2 mL). The mixture was stirred at rt for 2 - 15 h followed by an aq. workup (CHCI3, sat. aq. Na2CO3 soln; Na2SO4).
Purification of the crude product by chromatography (FC, normal phase or reversed phase prep. HPLC) afforded a macrocyclic N-acyl amine.
A.2: Amide coupling of a macrocyclic carboxylic acid with an amine and HATU
A soln of a macrocyxclic carboxylic acid (0.12 mmol), an amine (1.2 equiv.), HATU
(1.5 equiv.) and HOAt (1.5 equiv.) in DMF (0.5 mL) was treated at 4 C with i-Pr2NEt (3.0 equiv.). The mixture was stirred at 4 C for 2 h. The mixture was distributed between CH2Cl2 and 1 M aq. HCI soln. The organic phase was washed (sat. aq.
NaCI
soln), dried (Na2SO4), filtered and concentrated.
Purification of the crude product by chromatography (FC, normal phase or reversed phase prep. HPLC) afforded a macrocyclic amide.
Procedure A.3: Urea formation with isocyantes or equivalents of isocyanates A soln of an amino macrocycle (free amine or hydrochloride; 0.1 mmol) in CH2Cl2(0.5 mL) was treated at rt for 2 - 15 h with an isocyanate (1.1 equiv.) (or with a succinimidyl carbamate (1.1 equiv.)) and i-Pr2NEt (3 equiv.) followed by aq.
workup (CHCI3, sat. aq. Na2CO3 soln; Na2SO4). The crude product was purified by chromatography (FC, normal phase or reversed phase prep. HPLC) to afford the targeted macrocyclic urea.
Procedure A.4: Carbamate formation with chloroformates At 0 C the chloroformate (1.1 equiv.) was added to a stirred mixture of CH2Cl2 (0.9 mL) and sat. aq. Na2CO3 soln (0.35 mL). The amino macrocycle (free amine or hydrochloride; 0.085 mmol) and H20 (0.75 mL) were added. The mixture was stirred at rt for 2 - 15 h followed by aq. workup (Et0Ac, sat. aq. NaHCO3 soln;
Na2SO4). The crude product was purified by chromatography (FC, normal phase or reversed phase prep. HPLC) to afford the targeted macrocyclic carbamate.
Procedure A.5: Sulfonamide formation with sulfonyl chlorides At 0 C a soln of an amino macrocycle (free amine or hydrochloride; 0.1 mmol) in CH2Cl2 (0.5 mL) was successively treated with triethylamine (3.0 equiv.) and the sulfonyl chloride (1.0 equiv.). The mixture was stirred at 0 C to rt for 2 -15 h. (In case of incomplete transformation, more sulfonyl chloride (1.0 equiv.) and auxiliary base (3.0 equiv.) were added and stirring continued.) Aq. workup (CHCI3, sat. aq.
Na2CO3 soln; Na2SO4) and purification of the crude product by chromatography (FC, normal phase or reversed phase prep. HPLC) afforded the targeted macrocyclic sulfonamide.
Procedure A.6: N-Alkylation by reductive amination A.6.1. N,N-Dimethylamino macrocycles by reductive amination To a soln. of the amino macrocycle (free amine or hydrochloride; 0.085 mmol) in DCE
(1.2 mL) was added formaldehyde soln (36.5% in H20; 5 equiv.) followed by NaBH(OAc)3 (4 equiv.). The mixture was stirred at rt for 4 h.
Aq. workup (Et0Ac, sat. aq. NaHCO3 soln; Na2SO4) and purification of the crude product by chromatography (FC, normal phase or reversed phase prep. HPLC) afforded a dimethylamino macrocycle.
A.6.2: Synthesis of tertiary amines by N-methylation of secondary amines At 0 C formaldehyde soln (36.5% in H20; 5 equiv.), acetic acid (1.2 equiv.) and NaBH(OAc)3 (4.0 equiv.) were added to a soln of the macrocyclic amine (0.25 mmol) in DCE (4 mL). The mixture was stirred at rt for 4 h followed by aqueous workup (CH2Cl2, sat. aq. NaHCO3 soln; Na2SO4). Purification of the crude product by chromatography (FC, normal phase or reverse phase prep. HPLC) afforded the desired N-methyl-N,N-dialkylamino macrocycle.
A.6.3: Synthesis of tertiary amines by reductive amination of secondary amines The aldehyde (1.5 equiv.) was added to a mixture of the macrocyclic amine (0.25 mmol) and THF (1.5 mL). The mixture was stirred at it for 1 h. Acetic acid (1.2 equiv.) and NaBH(OAc)3 (3 equiv.) were added and stirring was continued for 15 h. (In case of incomplete transformation, more aldehyde (0.5 equiv.) was added and stirring continued.) After aqueous workup (CH2Cl2, 1 M aq. Na2CO3 soln; Na2SO4) the crude product was purified by chromatography (FC, normal phase or reverse phase prep.
HPLC) to afford the macrocyclic tertiary amine.
A.6.4: Synthesis of secondary amines by reductive amination Activated molecular sieve powder (3 A; 2 mg per mg of starting material) was added at rt to a soln of an amino macrocycle (0.1 mmol) and an aldehyde (1.1 equiv.) in THF (0.5 mL). The suspension was stirred for 2 - 4 h at rt, followed by the addition of acetic acid (1.1 equiv.) and NaBH(OAc)3 (3.0 equiv.). The mixture was stirred for 18 h and filtered. Aqueous workup of the filtrate (CH2Cl2, sat. aq. Na2CO3 soln;
Na2SO4) and purification of the crude product by chromatography (FC, normal phase or reverse phase prep. HPLC) afforded the alkylamino macrocycle.

Deprotection reactions Procedure B
Procedure B.1: Boc cleavage A soln of a macrocyclic Boc-amine in dioxane (1 mL per 100 mg) was treated with 4 M HCI in dioxane (1 mL per 100 mg) and stirred at rt for 2 - 16 h. The volatiles were evaporated. The residue was taken up in CHCI3, concentrated and dried i.v..
Solid residues were then washed with Et20/CH2C12.
Procedure B.2: tert.-Butyl ester cleavage or Boc cleavage Tert.-Butyl ester cleavage:
TFA (1 mL per 100 mg) was slowly added to a soln of a macrocyclic tert.-butyl ester in CH2Cl2(5 mL per 100 mg). The mixture was stirred for 2 h at rt and concentrated.
The residue was twice taken up in toluene and concentrated. The residue was then twice taken up in CHCI3 and concentrated followed by washing with Et20/CH2C12.

Boc cleavage:
TFA (1 mL per 100 mg of starting material) was slowly added to a soln of the macrocyclic Boc-amine in CH2Cl2 (3 mL per 100 mg). The mixture was stirred at rt for 3 h and concentrated. The residue was dried i.v.
Procedure B.3: Cbz cleavage A soln of the macrocyclic benzyl carbamate (500 mg) in Me0H (10 mL) or 2,2,2-trifluoroethanol (10 mL) was hydrogenated for 4 h at rt and at normal pressure in the presence of palladium hydroxide on activated charcoal (moistened with 50% H20;

¨ 20% Pd; 0.1 g). The mixture was filtered through a pad of celite. The residue was washed (Me0H). The combined filtrates and washings were concentrated to obtain the macrocyclic amine.
Procedure B.4: Nitro reduction A soln of the macrocyclic arylnitro compound (50 mg) in Me0H (5 mL) was hydrogenated for 15 h at rt and at normal pressure in the presence of platinum (IV) oxide hydrate (5 mg). The mixture was filtered through a pad of celite. The residue was washed (Me0H). The combined filtrates and washings were concentrated to obtain the macrocyclic aniline.
B.5: Methyl ester cleavage A soln of the macrocyclic methyl ester (0.07 mmol) in DCE (2 mL) was treated with trimethyltin hydroxide (3 equiv.) at 80 C for 16 h. Aqueous workup (CH2Cl2, 1 M aq.
HCI soln; Na2SO4) and purification by reverse phase prep. HPLC afforded the corresponding macrocyclic carboxylic acids.

Procedures for the synthesis on solid support Procedure C: Description of examples of core 10 and core 11 Procedure D: Description of examples of core 01 Synthesis of final products Advanced macrocyclic intermediates and final products depicted in Tables 13-31 (related cores cf. Scheme 23) were prepared starting from the suitable precursor macrocyclic acid, macrocyclic amine, or macrocyclic alcohol applying the general procedures (A.1¨A.6; B.1-13.5) or specific procedures described above (as indicated in the corresponding Tables). Deviations from general procedures are indicated in Tables 13a-31a.
Final products of Core 01 prepared on solid support were obtained following the general procedure D (vide supra; Core 01: Synthesis of final products on solid support).
Final products of Cores 10 and 11 were prepared following the general procedure described in the text (vide supra; Procedure C.1: Core 10: Synthesis of Ex.193a,c-h and Ex.194b and Procedure 0.2: Core 11: Synthesis of Ex.195a,b,e-h,j;
Ex.196c,i,k and Ex.197d) Analytical data of these intermediates and final products are depicted in Tables 13b-31b.
I UPAC names of all examples are listed in Tables 13c-31c.
The generic macrocyclic ring structures (Cores) related to Tables 13-31 are depicted in Scheme 23 in the order of their core numbers Reagents used in the derivatizations are commercially available with the exception of few N-succinimidyl carbamates which were synthesized from amines, anilines or heteroaryl amines according to the procedure of K. Takeda et al. Tetrahedron Lett.
1983, 24, 4569 ¨4572.
The synthesis of selected advanced intermediates and final products is described in detail in the text above; cf. corresponding core description.

The generic macrocyclic ring structures (Cores) related to Tables 13-31 are depicted in Scheme 23 in the order of their core numbers. 0 IV
CZ, I-µ

-,.
I-, Table 13a: Examples of Core 01 (Ex.1-Ex.14 and Ex.330-Ex.340; continued on the following page) t..) C.' Starting General No RA RB Reagent Purification Method Yield (isolated salt) Material Proced.
Ex.1-Ex.3 and Ex.330-Ex.331: cf. experimental description , 0 0 o 1-Naphthaleneacetic Ex.4 '4 1 MI go -,1--' - Ex.2 A.1.1; 1) acid FC (hexane/Et0Ac) 77%
0 iiiquant. P
Ex.5 ''N 10 NH2 Ex.4 B.1; 1) HCI-dioxane crude product (1-1CI salt) c, ,,, .3 , .

Ex.6 so 0 .. = A Ex.5 A.4 Methyl chloroformate FC
(CH2C12./Me0H) 82%
..
..
., N
H gill ' N 0.---c, , H
¨
co ..
, iii , 0 .
Ex.7 .'r, ¨go H Ex.5 A.1.1 ; 1>
1-Pyrrolidineacetic acid FC (CH2C12/Me0H) 71% ' ,-, 1. 1-Pyrrolidineacetic Ex.7 0 dm 'N').1 -,r1 lo ' H "-N -7 133 D ; 1) acid 2. 1-Naphthaleneacetic prep. HPLC method 1a 15% (TFA salt) acid Ex.8 0 a ''N .11, N (CH3)2 H Ex.5 A.6.1 Formaldehyde (36.5% in H20) FC (CH2C12/Me0H) 79% od e) )-it HCI-dioxane 97% r.a Ex.9 NH2 NH2 Ex.2 B.1 crude product 1--, rt, 16 h (HCI salt) f..4 ul vl c..) c, , , Starting General , No RA RB Reagent Purification Method Yield (isolated salt) k-4 Material Proced.
.
c..) ¨
2-Naphthaleneacetic FC )--, w , Ex.10 '-N10 40 ., so H N Ex.3 A.1.1 acid (hexane/Et0Ac/Me0H 31% C.' -..) H
4 C, 1 h 80 :20 :0 to 0 :90 :10) . .
Ex.11 NH2 -1, Hz, Pd(OH)2-C, 0 4* Ex.10 B.3 crude product 90%
H
2,2,2-trifluoroethanol Ex.12 4* Ex.11 A.1.1 o (Dimethylamino)acetic prep. HPLC method 48%
-.N.J-NI ,,N
p , , H H acid lb (TEA salt) .
,,, .3 0 C, 2 h .
.., o .
3-Methylbutanoic acid prep. HPLC method Ex.13 '-iv) '-i-i I" Ex.11 A.1.1 55% N) .
H
--..1 .

' Ex.14 'm110 40 ...NI., 0 Ex.3 A.4 1) Phenyl chloroformate EC (Et0Ac) 96%

1. Imidazol-1-yl-acetic Ex.332 _ 0 ra 0 1,-_-N, acid prep.
HPLC method -II giro ,..eõ..N,..." 133 D; 1) 2. 1-Naphthaleneacetic 1 a 48% (TEA salt) acid It I. 2,5-Dioxopyrrolidin- n bi , 1-y1 pyridin-3- ro , Ex.333 .. 0 am prep. HPLC method 1,..) 'N 10 65% (TFA salt) .N[1 --, H ',... N 133 D; 1) ylcarbamate la w 2. 1-Naphthaleneacetic ul cm w acid o, oo Starting General No RA RB Reagent Purification Method Yield (isolated salt) r.1 Material Proced.
c.
1-, (..,) i-, 1. 1-Pyrrolidineacetic (.4 . di N., c, 0 acid prep. HPLC method N ''''r. CI

Ex.334 H ='1\1,k,...0 133 D; 1) 38% (TFA salt) H 2. 3-Chlorophenylacetic la acid 1. 1-Pyrrolidineacetic o acid prep. HPLC method Ex.335NKN 133 D; 1) 26% (TFA salt) H H 2.
Cyclohexylacetic la P
acid .
N) .3 1. 1-Pyrrolidineacetic cn .., acid prep. HPLC method .
Ex.336--N1N 0 = -3,...-0 133 D; 1) 13% (TFA salt) r., H H 0 I) 2. 1-Naphthyl la ¨
co , , co .
1 isocyanate 1. 1-Pyrrolidineacetic 'LP 40 --1,1) ,0 133 D acid prep. HPLC method Ex.337 ''N'S
21% (TFA salt) 1 H H 2.
Benzylsulfonyl la i chloride ' 1-Pyrrolidineacetic acid ot Ex.338 i-PrzNEt (5 equiv.) r) A 0 0 õNLO Ex.3 A.1.3 EC (CH2C12/Me0H) 80% )- , . .,-H
Workup: CH2C12, sat. hl L.) o aq. NaHCO3 soln 1--µ

w --.
o Ex.339 ....
1 NH2 N--"'"-"" Ex.338 B.3 Hz, Pd(OH)2-C, Me0H crude product 983/0 uil w H
0n , i Starting General No RA RB Reagent Purification Method Yield (isolated salt) tv 1 Material Proced.
cz ,-, f.,.) ,-, 1-Naphthaleneacet L.) i --NI 0 aldehyde, 3h; FC (CH2C12/Me0H) cf, Ex.340 H 0 ' 'NLN Ex.339 A.6.4 N8BH(OAc)3 (3 eq.) and prep. HPLC 20% (TEA salt) H
Workup: CHCI3, sat. aq.
method 1a NaHCO3 soln 1) Cf. experimental description for detailed procedure P
.
N) , Table 13b: Examples of Core 01 (Ex.1-Ex.14 and Ex.330-Ex.340; continued on the following page) ..' Monoisotopic Rt (purity at [M+1-11+ Eso No RA RA RB
Formula LC-MS-Method co .
Mass 220nm) found , , ., 1 Ex.1-Ex.3 and Ex.330-Ex.331: of experimental description , . 0 (F;
Ex.4 N 0 --ni}c.o-"\N- C39H42N406 662.3 2.27 (86) 663.2 method 1a Ex.5s 0 is NH2 C341-134N404 562.3 1.61 (91) 563.2 method la 0, Ex.6 0 -, iii -.N.11-,0,-- C36H36N406 620.3 2.01 (90) 621.0 method 1a r) i-i H
w cz 0 ,,,õ 0 (.4 Ex.7 -',1 0 0 ,A
-H---- C40H43N505 673.3 2.13 (99) 674.3 method 2c 'a in (..) (.4 o, s, 0 a Ex.8 N "TS N(CH3)2 C36H38N404 590.3 1.65 (97) 591.1 method la H
' No RA RB Formula Monoisotopic Rt (purity at [M+1-1]+ LC-MS-Method Mass 220nm) found c...) Ex.9 NH2 NH2 C22H26N403 394.2 1.01 (96) 395.2 method 1a \o 0, Ex.10 0 C42H40N406 696.3 2.25 (91) 697.1 method la µ":11-'0 H ,1 Ex.11 NH2 =N0 SO C34H34N404 562.3 1.73 (91) 563.1 method 1a H

Ex.12 'N--)(*N-' 00 40 C38H41N505 647.3 1.71 (96) 648.1 method la H
y ,,Nt, õN 0 00 P
Ex.13 C39H42N405 646.3 2.09 (89) 647.2 method la .
r., H
cm H
,J
Ø
, I
, Ex.14 -.Ili 0..N10 I. C37H36N407 648.3 2.22 (97) 649.1 method la ' ..
H
O' 0 Am co .
, Ex.332 = N Wildlikt -'N.11A,/ C39H38N605 '1' 11.11 H 670.3 1.84 (99) 671.3 method 2c o .
i/
Ex.333 ' 04 0 = 1 -01 C40H38N605 682.3 1.94 (99) 683.2 method 2c 'N N
'"
Ex.334N,Y ., 0 C36H40CIN505 657.3 2.08 (99) 658.2 method 2c , 'N CI
H H

. , MD ,,NL 0 Ex.335 C36H47N505 629.4 2.10 (99) 630.3 method 2c , 'I\1 H H
"tJ1 r) , , Ex.336 H H 0 ''Nj)4) C39H42N605 674.3 2.09 (98) 675.3 method 2c tt , *0 1,4 H

r+
Ca , LO
tit 0õ0 Ex.337 -',S' 0 H C35H41N506S 659.3 1.59 (99) 660.3 method 1a (..J
0, oo H
, No RA RB Formula Monoisotopic Rt (purity at [M+Fl]+ LC-MS-Method k...) o Mass 220nm) found --, w , )--, w CSN
Tor,0 ,,..(0,-ID
Ex.338 N C36H41N506 639.3 1.63 (99) 640.2 method la H
Ex.339 NH2 -.N.Y.,0 C28H35N504 505.3 1.15 (97) 506.2 method 1c , H
=

' , eliiii Ex.340 ' 1 ti-=II = = Ny)CL,-0 C40H45N504 659.3 1.60 (87) 660.3 method la H
P
.3 , Table 13c: Examples of Core 01 (Ex.1-Ex.14 and Ex.330-Ex.340; continued on the following page) , , VD
No RA RB IUPAC name iL
smi jc 0 ,NII01 benzyl N-[(12R,16S,18S)-16-Rtert-butoxycarbonyl)aminol-8,13-dioxo-20-oxa-9,14-Ex.1 H diazatetracyclo[1 9.3.1.02,7.014,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-ylicarbamate tert-butyl N-[(12R,16S,18S)-12-amino-8,13-dioxo-20-oxa-9,14-Ex.2 NH2 ',N=c-\=-, ;
= benzyl N-[(12R,16S,18S)-161-H \
diazatetracyclo[19.3.1.02,7.04aj mipineon-amino -8,1 -2),02_,04x,6a,..291,1,243_-hexaen-16-yl]carbamate n Ex.3 I 0 NH2 o=
diazatetracyclo[19.3.1.02,7.014,11pentacosa-1(25),2,4,6,21,23-hexaen-12-yl]carbamate tt ti I 0 40 I ,z0 i tert-butyl N-[(12R,16S,18S)-12-{[2-(1-naphthyl)acetyl]amino}-8,13-dioxo-20-oxa-9,14- b.) c' ,--, Ex.4 õ
N
H ,,, I ' FNii - \-' diazatetracyclo[19.3.1.02,7.014,18]pentacosa-1(25),2,4,6,21,23-hexaen-16-yl]carbamate (.4 u, u, c, ot , , , No RA RB IUPAC name r.a c, ,-, N-[(l2R,16S,18S)-16-amino-8,13-dioxo-20-oxa-9,14-w Ex.5 , 0 .
,-, w NH2 diazatetracyclo[19.3.1.02,7.014,19pentacosa-1(25),2,4,6,21,23-hexaen-12-y1]-2-(1-, '11 40 c, , naphthyl)acetamide , o 40 , A "... methyl N-[(12R,16S,18S)-12-([2-(1-naphthypacetyl]amino}-8,13-dioxo-20-oxa-9,14-Ex.6 i -[1 411 Ti., 0 diazatetracyclo[l 9.3.1.02,7.014,18] pentacosa-1(25),2,4,6,21,23-hexaen-16-yUcarbamate o N-[(12R,16S,18S)-8,13-dioxo-16-{[2-(1-pyrrolidinyl)acetyl]annino}-20-oxa-9,14-Ex.7 H 40 -,1LO
diazatetracyclo[19.3.1.02,7.014,19pentacosa-1(25),2,4,6,21,23-hexaen-12-y1]-2-(1-P
naphthyl)acetamide o "
, .3 N-[(12R,16S,18S)-16-(dimethylamino)-8,13-dioxo-20-oxa-9,14-, Ex.8 , 0 0 -,N, 40 N(CH3)2 diazatetracyclo[l 9.3.1.02,7.014,19pentacosa-1(25),2,4,6,21,23-hexaen-12-y1]-2-(1-Zil ' "
, , naphthyl)acetamide , , (12R,16S,18S)-12,16-diamino-20-oxa-9,14-diazatetracyclo[19.3.1.02,7.014,19pentacosa-.
Ex.9 NH2 NH2 I 1(25),2,4,6,21,23-hexaene-8,13-dione benzyl N-[(12R,16S,18S)-16-{[2-(2-naphthypacetyl]amino}-8,13-dioxo-20-oxa-9,14-Ex.10'-ri Y 0 -N 4001 H
diazatetracyclo[19.3.1.02,7.014,11pentacosa-1(25),2,4,6,21,23-hexaen-12-yUcarbamate N-[(12R,16S,18S)-12-amino-8,13-dioxo-20-oxa-9,14-*ci Ex.11 NH2 -, 0 OW diazatetracyclo[19.3.1.02,7.014,11pentacosa-1(25),2,4,6,21,23-hexaen-16-y1]-2-(2- n i-H
M
, naphthyl)acetamide It 1,4 , o 1 2-(dimethylamino)-N-[(12R,16S,18S)-16-{[2-(2-naphthyl)acetyl]amino}-8,13-dioxo-20-oxa- ,--, w Ex.12 'N "."-N =-=-.

Ch H H 9,14-diazatetracyclo[l 9.3.1.02,7.014,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-yllacetamide (.11 4) No RA RB , IUPAC name 0 IN) cz Ex 13 N 3-methyl-N-[(12R,16S,18S)-16-{[2-(2-naphthyl)acetyl]amino}-8,13-dioxo-20-oxa-9,14- w ' `N "17.."--- '' )--, ca H H
diazatetracyclo[19.3.1.02,7.014,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-yl]butanamide vz o, ^-4 Ex.14 'III 0 --NI.. benzyl N-[(12R,16S,18S)-8,13-dioxo-16-Rphenoxycarbonyl)amino]-20-oxa-9,14-H
diazatetracyclo[19.3.1.02,7.014,187 ipentacosa-1(25),2,4,6,21 ,23-hexaen-12-yl]carbamate Ex.330 N10 ,,,.. ,,Nlo i ally' N-[(12R,16S,18S)-16-Rfert-butoxycarbonyl)amino]-8,13-dioxo-20-oxa-9,14-'H H - \''.
diazatetracyclo[19.3.1.02,7.014,11pentacosa-1(25),2,4,6,21,23-hexaen-12-yl]carbamate 'ally' N-[(12R,16S,18S)-16-amino-8,13-dioxo-20-oxa-9,14-Ex.331 '-NYL-0-",%

H
diazatetracyclo[19.3.1.02,7.014,11pentacosa-1(25),2,4,6,21,23-hexaen-12-yl]carbamate o "
.3 . 2-(1H-imidazol-1-y1)-N-[(12R,16S,18S)-12-{[2-(1-naphthyl)acetyl]amino)-8,13-dioxo-20-o , ifb r="
Ex.332 --ii -740 ,..N5),,N,i oxa-9,14-diazatetracyclo[19.3.1.02,7.014,18]pentacosa-1(25),2,4,6,21,23-hexaen-16- .
"

, , yliacetamide o..) .
, , N-[(12R,16S,18S)-8,13-dioxo-16-{[(3-pyridinylamino)carbonyl]amino}-20-oxa-9,14-.
0 rib Ex.333 --,1 10 ..,I r0 diazatetracyclo[19.3.1.02,7.01408]pentacosa-1(25),2,4,6,21,23-hexaen-12-y1]-2-(1 -, naphthyl)acetamide 2- 3-chloro hen 1 -N- 12R,16S,18S -8,13-dioxo-16- 2- 1- rrolidin 1 acet 1 amino -20-( P Y ) [( ) ([ ( PY Y ) )1] }
Ex.334 -.NI 0 0 -11 a oxa-9,14-diazatetracyclo[19.3.1.02,7.014,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-H
/t , yl]acetamide (-) )--3 Ex.335 ..fiLsxj , 2-cyclohexyl-N-[(12R,16S,18S)-8,13-dioxo-16-{[2-(1-pyrrolidinyl)acetyljamino}-20-oxa- t -'1\1 k=.) '1\r''.."-H H 9,14-diazatetracyclo[19.3.1.02,7.014,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-yl]acetamide w e u, (J1 W

, .

No RA RB
IUPAC name k=.) cz , ,-, N-[(12R,16S,18S)-12-{[(1-naphthylamino)carbonyljamino}-8,13-dioxo-20-oxa-9,14-w , I
Ex.336 - -ri ri 10,,NLO
diazatetracyclo[19.3.1.02,7.014,18]pentacosa-1(25),2,4,6,21,23-hexaen-16-yI]-2-(1-w e-, H

pyrrolidinyl)acetamide N-[(12R,16S,18S)-12-[(benzylsulfonyl)amino]-8,13-dioxo-20-oxa-9,14-Ex=337 = ,,c)''s"' I* '-NLO
diazatetracyclo[19.3.1.02,7.014,18, jpentacosa-1(25),2,4,6,21,23-hexaen-16-yI]-2-(1-'P-H
pyrrolidinyl)acetamide rq, 0 0 , (13 0 benzyl N-[(12R,16S,18S)-8,13-dioxo-16-{[2-(1-pyrrolidinypacetyljamino}-20-oxa-9,14-Ex 338 =N--'''' -- IS -H
diazatetracyclo[19.3.1.02,7.014,18, jpentacosa-1(25),2,4,6,21,23-hexaen-12-ylicarbamate p N-[(12R,16S,18S)-12-amino-8,13-dioxo-20-oxa-9,14-, Ex.339 NH2 ',N-Lr diazatetracyclo[19.3.1.02,7.014,18]pentacosa-1(25),2,4,6,21,23-hexaen-16-y1]-2-(1- rõ
H
8 r o.

pyrrolidinyl)acetarnide , , N-[(12R,16S,18S)-12-{[2-(1-naphthyl)ethyl]amino)-8,13-dioxo-20-oxa-9,14-.
Ex.340diazatetracyclo[19.3.1.02 46 7.0 14,18i jpentacosa-1(25),2,4,6,21,23-hexaen-16-yI]-2-(1-.T, '-NK--0 , , pyrrolidinyl)acetamide Pt Table 14a: Examples of Core 02 (Ex.15-Ex.40; continued on the following pages) c=-) 1-e m Starting General Purification t$
No RA RB Reagent Yield (isolated salt) 1,4 c, Material Proced.
Method w O-Ex.15-Ex17: cf experimental description cA
cn ca , Ex.18 = 00 Ex.17 A.1.1; 4) 2-Naphthaleneacetic acid FC (Et0Ac) 79% cy, , Ti 0 so õI

Starting General Purification 0 No RA RB Reagent Yield (isolated salt) t.) Material Proced.
Method o ,¨

(.4 w Ex.19 NH2 -1,1 41110 Ex.18 B.3; 4) H2, Pd(OH)2-C crude product 97% sr, C.' Me0H
--.1 FC
Ex.20 ''NK-k. --N 416 Ex.19 A.1.1; 4) 2-(Dimethylamino)acetic acid 30%
H H
(CH2C12/Me0H) Cyclopropanesulfonyl i chloride (1.5 equiv.) P
c) Et3N (3 equiv.) FC (Et0Ac; then c, Ex.21 ' --'s' - 00 Ex.19 II ." A.5 DMAP (0.1 equiv) CH2C12/Me0H) 86% N) .3 -, CHCI3 (0.25 mL), 50 C, 15 h .
N) .
Workup: CH2Cl2, half-sat. aq.
, c.y1 .
NaHCO3 soln.; Na2SO4 '2.7 N-Succinimidyl N-, methylcarbamate i , 0 , (1.3 equiv.) FC
Ex.22 = NAN .-' 100 Ex.19 A.3 63%
'" il H H i-Pr2NEt (3 equiv) (CH2C12/Me0H) THF/CHC13 1:1 (1.0 mL) rt, 3 h r) =-i Ri 2-Methoxyacetyl chloride (1.5 tl FC
I.) Ex.23 --NL0'= --: 00 Ex.19 A.1.2 equiv.) 51% cz 1-.
H
(CH2C12/Me0H) --..
rt, 3 h , ul c, oo , , , =
Starting General Purification 0 , No RA RB Reagent Yield (isolated salt) IV
Material Proced.
Method 1.-ca i-, 3-Methylbutanoyl chloride w aN
' (1.2 equiv.) ,..1 prep. HPLC
Ex.24 -,N.--J\ -- 0 *lb Ex.19 ,, A.1.2 0 C, 2 h 73%
H
H method 1a (Mixture was concentrated , without addn of Me0H.) , Ex.25 . 00 i** Ex.19 A.1.2; 4) Phenylacetyl chloride prep. HPLC 60%
'1,1 H H
method la P
, o ,111 0 õN. 4* Ex.19 prep. HPLC .
Ex.26 A.1.2; 4) Benzoyl chloride 67 /0 "
0, method 1a .., tO
.1=.
Butyryl chloride .
(1.2 equiv.) co .
, o prep. HPLC
,,, Ex.27 -.N.A,,, .1`) 0111 Ex.19 A.1.2 0 C, 2 h 67% ' ,-, H
method 1a ,,,, (Mixture was concentrated , without addn of Me0H.) Pentanoyl chloride (1.2 equiv.) :
prep. HPLC
Ex.28 ..1\ I '1 J.'"'''".-' ' 0 10101 Ex.19 A.1.2 0 C, 2 h 66%
H
.N method 1a id (Mixture was concentrated r) without addn of Me0H.) iz1 k=.) c, 1...
w ---, o = ,N.r,OH
prep. HPLC e tn Ex.29 'N"''''' Fl II Ex.40 1) LiOH 1) 47% ul W
H
0 method 1a o, , Starting General Purification 0 No RA RB Reagent Yield (isolated salt) k..) Material Proced.
Method cz )--, c.,.) s prep. HPLC *.µ
c..) Ex.30 --,,-?1-....-IL1Arr - Ex.39 2) Methyl isothiocyanate 2) 48%
H.0 0, .1 method 1a .0 FC (CH2C12/Me0H
Ex.31 = 1 -( 3 L.-rL --N:1,--sH Ex.32 3) 3) 57%
'I-1 H
100:0 to 80:20) 2-(Tritylthio)acetic acid .
i-Pr2NEt (5 equiv.) FC (CH2C12/Me0H
' Ex.32 , N 5....) , N... .,N5,SC(Ph), Ex.39 A.1.1 0 C, 2 h 85%
H H
90:10) p Workup: CH2Cl2, sat. aq.
.
r., .3 NaHCO3soln .., , .
N-Succinimidyl N-o methylcarbamate prep. HPLC
Ex.33 - Y.1,,,,ni, - Ex.39 A.3 77% (TFA salt) ---4 1 'N -F1AN
(1.4 equiv.) method la ,1 i-Pr2NEt (5.0 equiv.) 2,5-Dioxopyrrolidin-1-y1-3-(dimethylamino)phenyl-'o prep. HPLC
Ex.34 = ,,,--U,.. -T1IN 40 ;- Ex.39 A.3 carbamate 77% (TFA salt) '121 method 1a (1.4 equiv.) i-Pr2NEt (5.0 equiv.) en .3 2-Naphthyl isocyanate ies prep. HPLC
c0 Ex.35 - Ltiv, YL 401 Ex.39 A.3 (1.4 equiv.) 77% (TFA salt) '1\I ''N il ta H
method la i-Pr2NEt (5.0 equiv.) ui vi c...) ON

[

, Starting General Purification 0 No RA RB Reagent Yield (isolated salt) k=.) Material Proced.
Method ,-, , c..) )...
Methanesulfonyl chloride c.4 (Dv() o 1 prep. HPLC
Ex.36 '-i\ri-r1 ''N' Ex.39 A.5 (1.3 equiv.) 64% (TEA salt) H H
method 1a Et3N (5 equiv.) Phenylmethanesulfonyl o 1 , Ex.37 .
=nrk-N-- --N X2 011/ Ex.39 A.5 chloride prep. HPLC 43% (TEA salt) H H (1.3 equiv.) method la Et3N (5 equiv.) P
FC
.

(Dimethylamino)acetic acid N) (CH2C12./Me0H/ , ' 0 1Workup: 0H2Cl2, 1 M aq. HCI
.
Ex.38 --N-k--N-- --Nlo+ Ex.16 A.1.3 conc. aq. NH3 86% .
r., H H soln; sat. aq.
NaHCO3soln, .
....
, soln co .
sat. aq. NaCI soln; Na2SO4 co , o 9552) dioxane quant.
Ex.39 -..N-J.N. NH2 Ex.38 B.1 crude product H rt, 2 h (HCI salt) PI I - OEt Ethyl glyoxylate FC (CH2C12/Me0H
Ex.40 --,,,-.--N,. 111 g Ex.39 A.6.4 37%
IAo (1.2 equiv.) 9:1) 1) A soln of the macrocyclic ethylester Ex.40 (63 mg, 0.11 mmol) in THF/Me0H 1:1(1 mL) was treated at 0 C for 2 h with 2 M aq. LiOH soln (0.16 mL, ot 0.32 mmol). The mixture was concentrated. The residue was treated with 1 M aq.
HCI soln and concentrated Purification by reverse phase prep. n .3 HPLC afforded Ex.29 (40 mg, 47%).
k4 o 2) Methyl isothiocyantae (6 mg, 0.11 mmol) was added to a soln of Ex.39 (50 mg, 0.078 mmol) and i-Pr2NEt (0.07 mL,0.39 mmol) in CH2Cl2 (0.5 mL). 1--, (...J
, O
The mixture was stired for 16 h at it. More methyl isothiocyantae (2 mg) was added and stirring continued for 1 h. Aq. Workup (CHCI3, sat. aq. tri ul c..4 Na2CO3 soln; Na2SO4) and purification by prep. HPLC (method 1a) afforded Ex.30 (26 mg, 48%).
w I
3) Triisopropylsilane (0.12 mL, 0.58 mmol) was added to a soln of Ex.32 (50 mg, 0.115 mmol) in CH2C12 (0.4 mL). The mixture was cooled to 0 C

t-..) followed by the addition of TEA (0.4 mL). The mixture was stirred for 30 min at 0 C and concentrated. FC (CH2C12/Me0H 100:0 to 80:20) afforded o )--, w -_.
Ex.31 (46 mg, 57%).
w o o, 4) Cf. experimental description for detailed procedure o Table 14b: Examples of Core 02 (Ex.15-Ex.40; continued on the following page) Monoisotopic Rt (purity at [M+Fl]F
No RA R8 Formula LC-MS-Method i Mass 220nm) found P

.
r., 1 Ex.15-Ex.17: cf experimental description .3 , I

I
Ex.18 'N()H 0110 C44H44N406 724.3 2.36 (98) 725.2 method 1a ..
N) Ex.19 NH2 C36H38N404 590.3 1.76 (97) 591.2 method la 8 , - N (0 i--µ
Ex.20 - Y-1,.......''.- - 4011* C40H45N505 'N -N 675.3 1.82 (95) 676.3 method 1a .
H H
Ex.21 . 694.3 2.10 (97) 695.2 method 1a - --'s' - =P
'11 11 O C39H42N406S

Ex.22 = -it. H 411110 C38H41N505 647.3 1.96 (98) 648.2 method la 1 'I\1 l\r- --ri H H

Ex.23 --N--- --- -; MOO C39H42N406 662.3 2.04 (99) 663.2 method 1a ot n H
.e , 5) Ex.24 = .-1.õ,L -. SOO C41H46N405 674.3 2.20 (98) 675.2 method 1a t$
IV , N
H

)--, C...) Ex.25 -'1,I 1411 = , 4140 C44H44N405 708.3 2.27 (99) 709.2 method la -...
o H H
CA
(J) (..) c"
Ex.26 --N ill.: 44 C43H42N405 694.3 2.26 (99) 695.2 method 1a oo H H

, No RA RB Formula Monoisotopic Rt (purity at [M-EF1]+ LC-MS-Method k..) cz Mass 220nm) found --, (..) --1-, (.4 Y
Ex.27 - -NL.,--..õ . 8 4110 C40H44N405 660.3 2.15 (99) 661.2 method la o, H

c Ex.28 --H-'L.,..- -; 00 C41H46N405 674.3 2.24 (99) 675.3 method 1a Ex.29=- 51Ji ''N--"e" C30H39N506 565.3 1.25 (99) 566.2 method 1 a r, -, H 0 U I
Ex.30 ' 'IV ' 'NN C30H40N604S 580.3 1.38 (95) 581.2 method 3a Ex.31 ,,Ni.,) ,.)... , _NLsH
C30H39N505S 581.3 1.49 (90) 582.0 method 1a P
H

Iv Ex.32 - ,NLIV, 11sc(ph), C49H53N505S 823.4 2.18 (90) 824.3 method 1a , H
Ø

Iv n) , Ex.33 - -NIL L' - 'NAV*
C30H40N605 564.3 1.40 (99) 565.1 method la o ..
, H

r Ex.34--11i....11. .N-2- 411,r- C37H47N705 669.4 1.37 (97) 670.2 method 1a .
Ex.35 ssivY- TIIN-00 C39H44N605 676.3 1.84 (98) 677.3 method 1a 0, ,0 U
Ex.36 --N-.. - - Ni=S'.-, C29H39N506S 585.3 1.44 (99) 586.0 method la H H
it Ex.37 ' -N)cU --N :µe 40 C35H43N506S 661.3 1.68 (97) 661.8 method le r) H H
*3 OF
M
Ex.38 --iv) --Nlo' C33H45N506 607.3 1.73 (93) 608.1 method 1a 1-es w H H
=
--, La Ex.39 --is)...JI, NH2 C28H37N504 507.3 1.23 (93) 508.2 method la -a-, tA
CJI
C.4 CT
Ex.40 --N-U. Yrt C32H43N506 593.3 1.38 (96) 594.1 method 1a coo H

, , Table 14c: Examples of Core 02 (Ex.15-Ex.40; continued on the following pages) w No RA RB I
UPAC name c.4 ,-(...) benzyl N-[(10S,12S,165)-12-Rtert-butoxycarbonyl)amino]-20-methyl-15,21-dioxo-8-oxa-a, Ex.15- 1 -. I .-=õ_ sN 101 N 0 14,20-diazatetracyclo[20.3.1.02.7.010,14]hexacosa-1(26),2,4,6,22,24-hexaen-16--.1 H
_ yl]carbamate tort-butyl N-[(10S,12S,16S)-16-amino-20-methyl-15,21-dioxo-8-oxa-14,20-Ex.16 NH2 H \
diazatetracyclo[20.3.1.027.010,14]hexacosa-1(26),2,4,6,22,24-hexaen-12-yl]carbamate - 1. benzyl N-[(10S,12S,16S)-12-amino-20-methyl-15,21-dioxo-8-oxa-14,20-Ex.17 -v, 0 si NH2 p diazatetracyclo[20.3.1.02,7.010,14]hexacosa-1(26),2,4,6,22,24-hexaen-16-yl]carbamate .
rõ
.3 benzyl N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino}-15,21-dioxo-8-oxa- , Ex.18 '1110 to --; 0116 14,20-diazatetracyclo[20.3.1.02,7.010,14Thexacosa-1(26),2,4,6,22,24-hexaen-16- rõ
o .
, yl]carbamate .
, , N-[(10S,12S,16S)-16-amino-20-methyl-15,21-dioxo-8-oxa-14,20-.

Ex.19 NH2 --Fla 40 diazatetracyclo[20.3.1.02,7.010,14]hexacosa-1(26),2,4,6,22,24-hexaen-12-y1]-2-(2-naphthyl)acetamide 2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-12-1[2-(2-naphthypacetyl]aminol-15,21-Ex.20 --N1..-L. -II 00 dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.02,7.01 .14Thexacosa-1(26),2,4,6,22,24-hexaen-16-H
't yllacetamide n )-.
, N-[(10S,12S,16S)-16-[(cyclopropylsulfonyl)amino]-20-methyl-15,21-dioxo-8-oxa-14,20- t o ,0 I.) o , Ex.21 -- OP diazatetracyclo[20.3.1.02,7.01 ,14Thexacosa-1(26),2,4,6,22,24-hexaen-12-y1]-2-(2- ,--, c..., , N "
O-, eA
i naphthyl)acetamide tA
t..) c., oc , No RA RB
IUPAC name t=.4 o N? IN II N-[(10S,12S,16S)-20-methy1-16-{Rmethylamino)carbonyl]amino)-15,21-dioxo-8-oxa-14,20-Ex.22 -0.
diazatetracyclo[20.3.1.02,7.010,14]hexacosa-1(26),2,4,6,22,24-hexaen-12-y1]-2-(2-c., H H
N.a --) naphthyl)acetamide 2-methoxy-N-R1 OS,12S,16S)-20-methy1-12-{[2-(2-naphthypacetyl]aminol-15,21-dioxo-8-Ex.23 - -N-1--- -- -, OW oxa-14,20-diazatetracyclo[20.3.1.02,7.01 ,14]hexacosa-1(26),2,4,6,22,24-hexaen-16-H H
yllacetamide 3-methyl-N-[(10S,12S,16S)-20-methy1-12-{[2-(2-naphthypacetyl]amino}-15,21-dioxo-8-oxa-Ex.24 , cin , 0 ollidik 'N'''''-' 'N IIIP 14,20-diazatetracyclo[20.3.1.02,7.010,14]hexacosa-1(26),2,4,6,22,24-hexaen-16- P
H H

0, yl]butanamide N-[(l0S,12S,16S)-20-methy1-15,21-dioxo-16-[(2-phenylacetyl)amino]-8-oxa-14,20-rõ
rv , o .
Ex.25 -, o 0 ,'11 0 SO
diazatetracyclo[20.3.1.02,7.010,1hexacosa-1(26),2,4,6,22,24-hexaen-12-y1]-2-(2-Iv ,1, H H
I
r naphthyl)acetamide 0, , 0 00 N-[(10S,12S,16S)-20-methy1-12-{[2-(2-naphthyl)acetyl]amino}-15,21-dioxo-8-oxa-14,20-Ex.26 'H 0 --N
H d iazatetracyclo[20.3.1.02,7.010,11hexacosa-1(26),2,4 ,6,22,24-hexaen-16-yl]benzami de Ex.27 'N - o Se N-[(I0S,12S,16S)-20-methy1-12-{[2-(2-naphthypacetyl]aminol-15,21-dioxo-8-oxa-14,20-H II
diazatetracyclo[20.3.1.02,7.010,1hexacosa-1(26),2,4,6,22,24-hexaen-16-ylibutanamide tl Ex 28 ,..N 0 , 0 400 N-[(1 OS,12S,16S)-20-methy1-12-112-(2-naphthypacetyl]amino}-15,21-dioxo-8-oxa-14,20- n i-i H
diazatetracyclo[20.3.1.02,7.010,14Thexacosa-1(26),2,4,6,22,24-hexaen-16-ylipentanamide ti r.) cz w 2-{[(10S,12S,16S)-16-{[2-(dimethylamino)acetyl]amino)-20-methy1-15,21-dioxo-8-oxa-, o col Ex.29 = -N1---N PI 11 14,20-d iazatetracyclo[20.3.1.02,7.010,11hexacosa-1(26),2,4,6,22,24-hexaen-12- CA
G.) V\

yliamino}acetic acid No RA RB IUPAC name w S 2-(dimethylamino)-N-[(10S,12S,16S)-20-methy1-12-{[(methylamino)carbothioyl]amino}- w ,¨
H
Ex.30 --N. N. = .NAN., 15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.027.010,14]hexacosa-1(26),2,4,6,22,24-cA
H
H H
-.) hexaen-16-yllacetamide 0 2-(dimethylamino)-N-[(10S,12S,16S)-20-methy1-15,21-dioxo-12-[(2-sulfanylacetyl)amino]-Ex.31-NS1-1 8-oxa-14,20-diazatetracyclo[20.3.1.02,7.010,14}hexacosa-1(26),2,4,6,22,24-hexaen-16-H H yl]acetamide 2-(d imethylamino)-N-[(10S,12S,16S)-20-methy1-15,21-dioxo-12-{[2-P
Ex.32 -,Ni)*(...,-, '-N,:i:LSC(Ph)3 (tritylsulfanyl)acetyl]amino}-8-oxa-14,20-diazatetracyclo[20.3.1.02,7.010,1hexacosa- .
0, 1(26),2,4,6,22,24-hexaen-16-yl]acetamide , 0 2-(dimethylamino)-N-[(10S,12S,16S)-20-methy1-12-{[(methylamino)carbonyl]amino}-15,21-c, , Ex.33='NAN-, dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.02,7.010,14Thexacosa-1(26),2,4,6,22,24-hexaen-16-H ' I
H H
, yl]acetamide .
2-(dimethylamino)-N-[(10S,12S,16S)-12-({[3-(dimethylamino)anilino]carbonyl}amino)-20-_IL I
Ex.34 -'1\1" -""--0 'N'' '1\11N IS N"-- methy1-15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.02,7.010,14Thexacosa-1(26),2,4,6,22,24-hexaen-16-yl]acetamide 2-(dimethylamino)-N-[(105,12S,16S)-20-methy1-12-{[(2-naphthylamino)carbonyl]amino}-t Ex.35 '-N)U '-NIN 01101 15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.02,7,010,14Thexacosa-1(26),2,4,6,22,24- n H
H H H
tt hexaen-16-yl]acetamide it b.J

2-(dimethylamino)-N-[(105,12S,16S)-20-methy1-12-Rmethylsulfonyl)amino]-15,21 -dioxo-8- ,--0, 0 cz Ex.36 -. Y, ' - :8'' N N "`= oxa-14,20-diazatetracyclo[20.3.1.02,7.010,1hexacosa-1(26),2,4,6,22,24-hexaen-16- cJi CA
t...) H H
c, yliacetamide No RA R8 IUPAC name 0 w cz ,--, N-[(10S,12S,16S)-12-Rbenzylsulfonyl)amino]-20-methyl-15,21-dioxo-8-oxa-14,20-c..) I 0,,o 0 .
.
c..4 Ex.37 --N-¨A-.. -.NS' diazatetracyclo[20.3.1.027.010,14]hexacosa-1(26),2,4,6,22,24-hexaen-16-yI]-2-,.:, c., H
(dimethylamino)acetamide 0 tert-butyl N-[(10S,12S,16S)-16-{[2-(dimethylamino)acetyl]amino}-20-methy1-15,21-dioxo-8-Ex.38 -'1\l'N' ''N)10 oxa-14,20-diazatetracyclo[20.3.1.02,7.010,14]hexacosa-1(26),2,4,6,22,24-hexaen-12-H
H
yl]carbamate N-[(10S,12S,16S)-12-amino-20-methyl-15,21-dioxo-8-oxa-14,20-O

Ex.39 ''r\i'\' NH2 diazatetracyclo[20.3.1.02,7.010,14]hexacosa-1(26),2,4,6,22,24-hexaen-16-y1]-2-.
, (dimethylamino)acetamide , I.
ethyl 2-{[(10S,12S,16S)-16-{[2-(dimethylamino)acetyliamino}-20-methyl-15,21-dioxo-8-,..........õ-OEt m , Ex.40 -,N.),.= .N. H 11 oxa-14,20-diazatetracyclo[20.3.1.02,7.010,14]hexacosa-1(26),2,4,6,22,24-hexaen-12-, r yl]aminolacetate .
I
Table 15a: Examples of Core 03 (Ex.41-Ex.67; continued on the following pages) Starting General No RE Reagent Purification Method Yield (isolated salt) i-c$
Material Proced.
n )-i Ex.41-Ex.42, Ex.62¨Ex.67: of experimental description V
n.) o 1--, w O-cm cm w i oo Starting General , No RE Reagent Purification Method Yield (isolated salt) r.a , Material Proced.
cD

c..4 NH4CI (4 equiv.) w .0 o, HATU (2.0 equiv.) .0 -...1 HOAT (2.0 equiv.) prep. HPLC method Ex.43 CONH2 Ex.42 A.2 i-Pr2NEt (6 equiv.) 64%

rt, 2 h Workup: Sat. aq.
Na2CO3, CH2Cl2 P
CH3NH3CI (4 equiv.) .
r., .3 HATU (2.0 equiv.) .
-, HOAT (2.0 equiv.) .
prep. HPLC method Ex.44 CONHCH3 Ex.42 A.2 i-Pr2NEt (6 equiv.) 71% n.) c) , , cn .
4 C, 1 h i 1 Workup: Sat.
aq.
Na2CO3, CH2Cl2 prep. HPLC method Ex.45 CONHPh Ex.42 A.2 Aniline 80%
, i IC;
prep. HPLC method tl , Ex.46 ,N Ex.42 A.2 Pyrrolidine 53% r) )-----) 3 t=1 0.0 r.) o ,-, w , o to, Cli W
0 \

1 Starting General o I No RE Reagent Purification Method Yield (isolated salt) w 1 Material Proced.
0, w N,N-Dinnethyl-o --, w .0 ,a ethylenediamine .0 I
prep. HPLC method 61%
Ex.47 ,-IL....---.õ,N Ex.42 A.2 (1.0 equiv.) ri 1a (TFA salt) Workup: Sat. aq.
Na2CO3, CH2Cl2 , ,11. ,.. tert.-Butyl-3-prep. HPLC method Ex.48 - N ¨ NHBoc Ex.42 A.2 65%
H
aminopropylcarbamate 3 P
HCI-dioxane 74% .
Ex.49 - IN '''''''N H2 Ex.48 B.1 crude product "
H rt, 2 h (HCI salt) .
.., o .
' ,IL
r., 1 Ex.50 - N '''k` Ex.42 A.2 1) 3-Picolylamine prep. HPLC method 37% m .
, 1 c (TFA salt) o .
, N
cr) o .
, prep. HPLC method , Ex.51 ,- It. N ----...._,O,, Ex.42 A.2 2-Methoxyethylannine 63%
H

Ex.52 IL A - Ex.42 A.2 Cyclopropylannine prep. HPLC method 84%
- N

H

2,2,2-prep. HPLC method Ex.53..
66% v NCF3 Ex.42 A2 T
n rifluoroethylamine H

4:1 r.) Ex.54 --ILN-"----' Ex.42 A.2 lsobutylamine prep. HPLC method 66% c' .., H
3 w --...

tn o tA
2-Aminoethanol prep. HPLC method w Ex.55 -II. -,N,..,,OH Ex.42 A.2 82% 0, oo - N
H 4 C 2 h and rt 3 h 1c Starting General o No RE Reagent Purification Method Yield (isolated salt) 1,4 Material Proced.
CD
.., CA
f -+
Glycine-tert.-butyl ester (.4 i µ.0 o.
hydrochloride ' --I
, (1.5 equiv.) ..11 o prep. HPLC method Ex.56 - Hon Ex.42 A.2 HATU 2.0 equiv.) 76%
HOAt (2.0 equiv.) i-Pr2NEt (3.0 equiv.) ' 4 C, 2 h P
Z
Ex.57 ,N,-,,,,oH
- " O Ex.56 B.2 TFA, CH2C12 crude product 80% .
r., o, .4 ..
0 (L)-a-..' prep. HPLC method "
Ex.58 - - l(N IN/ Ex.42 A.2 Methylbenzylamine 55% n, , ..
, H
3 o 4 C 2 h and rt 2 h .

I N,N,N'-FC (CH2Cl2/ Me0H/
Ex.59 õ11.N.--,..õ,,1\1,, Ex.42 A.2 Trimethylethylene- 83%
aq. NH3 soln) 1 I diamine , H
-..,..,,N

II
Naphthalen-1- prep. HPLC method Ex.60 o so Ex.42 A.257% ro ylmethanamine 3 (-) i.i ro r.) ,-, (.4 vl cm w 0\
oo , , , Starting General No RE
Reagent Purification Method Yield (isolated salt) w Material Proced.
,-, w, prep. HPLC method --, w N H
o, ---.) Naphthalen-2-Ex.61 1110411 Ex.42 A.2 ylmethanamine and 29%
prep. HPLC method 2a 1) Cf. experimental description for detailed procedure P
Table 15b: Examples of Core 03 (Ex.41-Ex.67; continued on the following pages) ,, .3 ., , Monoisotopic Rt (purity at ..
No RE Formula [M+FI]. found LC-MS-Method ,,) Mass 220nm) C
..
, co .
Ex.41-Ex.42, Ex.62-Ex.67: cf. experimental description 47 ., Ex.43 CONH2 C23H27N305 425.2 1.47 (95) 426.1 method 1a Ex.44 CONHCH3 C24H29N305 439.2 1.49 (99) 440.1 method la Ex.45 CONHPh C29H31N305 501.2 1.97 (97) 502.1 method la , (21 1 Ex.46 ,N C27H33N305 479.2 1.74 (98) 480.1 method 1a , Jci ----) n 1-i o I
to Ex.47 -.11.N.õ---..,. N., C27H36N405 496.3 1.32 (99) 497.2 method 1a t.1 o H
1--, w Ex.48 õJct -.. -N - NHBoc 031H42N407 582.3 1.91 (99) 583.1 method la vl ul w CL
Ex.49 --INN H2 C26H34N405 482.2 1.32 (95) 483.1 method 1a c:\
oo H
, , Monoisotopic Rt (purity at No RE Formula [M+Hp- found LC-MS-Method k..) e=
1-, Mass 220nm) c.4 _ o c..) .IL.cr, , Ex.50 - N---""'"..-% 029H32N405 516.2 1.32 (99) 517.1 method 1a H I

Ex.51k . ,.,.0 C26H33N306 483.2 1.57 (95) 484.1 method 1a ' N
H
, 0 Ex.52 -- I.NA C26H31N305 465.2 1.67 (99) 466.1 method la H
P

.
Ex.53 - C25H28F3N305 507.2 1.80 (94) 508.0 method la ' IL'N---'"CF3 ..J
H
..
..

Ex.54 -Ji.
- N C27H35N305 481.2 1.85 (95) 482.1 method la Ni cp .
, ..
, co ,D
H' o .
Ex.55 ',I-1,N,--,,OH C25H31N306 469.2 1.40 (94) 470.1 method la H
c ,1)( Ex.56 . N.-1_0,k C29H37N307 539.3 1.91 (93) 540.0 method la E4 o I

Ex.57 OH C25H29N307 483.2 1.47 (85) 484.1 method la - rici It c") )-3 rt 'a Ex.58 IL hi 41101 C31H35N305 529.2 2.00 (93) 530.1 method la õ
t..) o ,--, t.4 sa--, o I
u*
ui t.., Ex.59 ,-11-.N-----...õ-N., C28H38N405 510.3 1.37 (97) 511.2 method 1a o, oo ' I

No RE Formula Monoisotopic Rt (purity at [M+1-1]+ found LC-MS-Method k=.) Mass 220nm) c.4 Ex.60 0 C34H35N305 565.2 2.09 (97) 566.1 method 1a NH

Ex.61 C34H35N305 565.2 2.12 (100) 566.1 method la ,õ
Table 15c: Examples of Core 03 (Ex.41-Ex.67; continued on the following pages) No RE IUPAC name benzyl (10R,15S)-4-methoxy-10,16-dimethy1-12,17-dioxo-8-oxa-11,16-Ex.41 CO2CH2Ph diazatricyclo[l 6.3.1.021d ocosa-1(22),2,4,6,18,20-hexaene-15-carboxyl ate (10R,15S)-4-methoxy-10,16-dimethy1-12,17-dioxo-8-oxa-11,16-Ex.42 CO2H
diazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaene-15-carboxylic acid (10R,15S)-4-methoxy-10,16-dimethy1-12,17-dioxo-8-oxa-11,16-Ex.43 CONH2 diazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide (10R,15S)-4-methoxy-N,10,16-trimethy1-12,17-dioxo-8-oxa-11,16-Ex.44 CONHCH3 diazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide GO

No RE
IUPAC name 0 w o --, , (10R,15S)-4-methoxy-10,16-dimethy1-12,17-dioxo-N-pheny1-8-oxa-11,16- w i I Ex.45 CONHPh ,-, w diazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide +c, c., 1/4c, ICI

r- (10R,15S)-4-methoxy-10,16-dimethy1-15-(1-pyrrolidinylcarbony1)-8-oxa-11,16-Ex.46 ,N
---) diazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaene-12,17-dione i ' (10R,15S)-N42-(dimethylamino)ethy1]-4-methoxy-10,16-dimethy1-12,17-dioxo-8-o I
Ex.47 ..-ILN.----N,, oxa-11,16-d iazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaene-15-P
carboxamide .
rõ
.3 tert-butyl N43-({[(10R,15S)-4-methoxy-10,16-dimethy1-12,17-dioxo-8-oxa-11,16-.
, i .
i Ex.48 - 5.-1,1---------- NHBoc diazatricyclo[16.3.1.02.1docosa-1(22),2,4,6,18,20-hexaen-15- rõ
H
r o.
yl]carbonyllamino)propyl]carbamate , Z (10R,15S)-N-(3-aminopropy1)-4-methoxy-10,16-dimethy1-12,17-dioxo-8-oxa-11,16-Ex.49 , , , --N-------N
, H H2 diazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide .10t. (10R,15S)-4-methoxy-10,16-dimethy1-12,17-dioxo-N-(3-pyridinylmethyl)-8-oxa-, Ex.50 - N'' El 1 . 11,16-d iazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide N
0 (10 R,15 S)-4-methoxy-N-(2-methoxyethyl)-10,16-d imethy1-12,17-di oxo-8-oxa-11,16-Ex.51 , - I'L N
e) H
diazatricyclo[16.3.1.02,7]docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide )-t Ex.52 -, k.NA (10R,15S)-N-cyclopropy1-4-methoxy-10,16-dimethy1-12,17-dioxo-8-oxa-11,16-,-, H diazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide w O-ul (10R,15S)-4-methoxy-10,16-dimethy1-12,17-dioxo-N-(2,2,2-trifluoroethyl)-8-oxa-w Ex.53, It. ...-...

H 11,16-diazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide I
No RE
1UPAC name 0 r.a ¨

1¨, (10R,15S)-N-isobuty1-4-methoxy-10,16-dimethy1-12,17-dioxo-8-oxa-11,16-w ,--, 1 Ex.54 _ - 11.N ...---.........õ--w , H diazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide c, ,.0 -.4 i (10R,15S)-N-(2-hydroxyethyl)-4-methoxy-10,16-dimethy1-12,17-dioxo-8-oxa-11,16-Ex.55 H diazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide tert-butyl 2-({[(10R,15S)-4-methoxy-10,16-dimethy1-12,17-dioxo-8-oxa-11,16-, Ex.56 --(1)Lh1"1-1-- - d iazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaen-15-yl]carbonyl}amino)acetate P
1 2-(( [(10R,15S)-4-methoxy-10,16-dimethy1-12,17-dioxo-8-oxa-11,16- 2, 1 Ex.571 l.
.., r.,r) OH diazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaen-15- .3 , t yl]carbonyllamino)acetic acid , .1, -..11..N (10R,15S)-4-methoxy-10,16-dimethy1-12,17-dioxo-N-R1 S)-1-phenylethy1]-8-oxa- .
, , Ex.58 .
1 H 161 11,16-d iazatricycl o[16.3.1.021docosa-1(22),2,4,6,18,20-hexaene-15-carboxa mide 0 I (10R,15S)-N42-(dimethylamino)ethy1]-4-methoxy-N,10,16-trimethy1-12,17-dioxo-8-Ex.59 ,-11--N--"-...,,,N., oxa-11,16-diazatricyclo[16.3.1.02J]docosa-1(22),2,4,6,18,20-hexaene-15-, I carboxamide , H
n - ,,...N
i-i ' II (10R,15S)-4-methoxy-10,16-dimethyl-N-(1-naphthylmethyl)-12,17-dioxo-8-oxa- m Ex.60 0 010 11,16-diazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide It =
)--, w , o cil cn ta oo No RE
1UPAC name (10R,15S)-4-methoxy-10,16-dimethyl-N-(2-naphthylmethyl)-12,17-dioxo-8-oxa-Ex.61 so11,16-diazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide k.c) (10R,15S)-15-(hydroxymethyl)-4-methoxy-10,16-dimethy1-8-oxa-11,16-Ex.62 CH2OH
diazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaene-12,17-dione (1 OR,1 5S)-4-methoxy-10,16-dimethy1-15-[(3-pyridinyloxy)methyl]-8-oxa-11,16-, Ex.63 diazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaene-12,17-dione (10R,15S)-15-(azidomethyl)-4-methoxy-10,16-dimethy1-8-oxa-11,16-Ex.64 CH2N3 diazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaene-12,17-dione (10R,15S)-15-(aminomethyl)-4-methoxy-10,16-dimethy1-8-oxa-11,16-Ex.65 CH2NH2 diazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaene-12,17-dione N-{[(10R,15S)-4-methoxy-10,16-dimethy1-12,17-dioxo-8-oxa-11,16-Ex.66 CH2NHCOCH2Ph diazatricyclo[16.3.1.02,1docosa-1(22),2,4,6,18,20-hexaen-15-yl]methy11-2-phenylacetamide [(10R,15S)-4-methoxy-10,16-dimethy1-12,17-dioxo-8-oxa-11,16-Ex.67 CH2OCONHPh diazatricyclo[16.3.1.021docosa-1(22),2,4,6,18,20-hexaen-15-yl]methyl N-phenylcarbamate , , Table 16a: Examples of Core 04 (Ex.68-Ex.89; continued on the following pages) , N) I Starting General Purification )¨

No RC Reagent Yield (isolated salt) w --..
e.
, Material Proced.
Method w Ex.68 -Ex.69: cf. experimental description CH3NH3CI (4 equiv.) HATU (2.0 equiv.) , HOAT (2.0 equiv.) FC
Ex.70 NHCH3 Ex.69 A.2 i-Pr2NEt (6 equiv.) 50%
(CH2C12/Me0H) rt, 2 h P
Workup: Sat. aq. Na2CO3, .

CH2Cl2 .
-.]
NH4CI (4 equiv.) ,--µ
HATU (2.0 equiv.) -7.µ
.
, .
, J
HOAT (2.0 equiv.) ' ,--µ
prep. HPLC
Ex.71 NH2 Ex.69 A.2 i-Pr2NEt (6 equiv.) 95 method 3 rt, 2 h Workup: Sat. aq. Na2CO3, i CH2Cl2 prep. HPLC
Ex.72 NHPh Ex.69 A.2 Aniline 68 Iv n method 3 .-.3 H
prep. HPLC )7:( Ex.73 40 N. , Ex.69 A.2 2-Phenylethylamine method 3 71 r..) c, )--f.4 H Naphthalen-1-prep. HPLC til -NI
CA
, W
, Ex.74 OS Ex.69 A.2 ylmethanamine method 3 70% c, co 0 C, 1 h and FC (Et0Ac) , ' ' ' Starting General Purification 0 No RC Reagent Yield (isolated salt) IV
Material Proced.
Method cz, 1-, w 3-Picolylamine w c7, Ex.75 Ex.69 A.2 4 C, 1 h prep. HPLC
-Th M
. 55%
--.1 N Workup: Sat. aq.
Na2CO3, method 3 ! CHC13 , õ
prep. HPLC
, Ex.76 Ersi 0 Ex.69 A.2 (L)-a-Methylbenzylarnine 60%
, method 3 , , prep. HPLC
Ex.77 '-N"--a-= Ex.69 A.2 2-Methoxyethylamine 66% p H
method 3 .
N) ' -prep. HPLC .
.., Ex.78 -1\1---'CF3 H Ex.69 A.2 2,2,2-Trifluoroethylamine 72% ..
..
method 3 r., rv .
, prep. HPLC
cri ..
, method 3 Ex.79 -'NA Ex.69 A.2 Cyclopropylamine then 32% ' , H
prep. HPLC
method 1a N- Isobutylamine prep. HPLC
Ex 80 H Ex.69 A.2 77%
4 C, 1 h method 3 oct n 2-Aminoethanol prep. HPLC
Ex.81 -.N.--,õoH
Ex.69 A.2 56% m H
4 C 2 h and rt 1 h method 1a od k.) c, c..J
, 'ee cm t...) o, oe , I
i ' , Starting General Purification 0 No RC Reagent Yield (isolated salt) r.4 Material Proced.
Method cz ,--, w , .., Glycine-tert.-butyl ester c..J
, hydrochloride i (2.2 equiv.) Ex.82 '*"-)fl Ex.69 A.2 HATU (2.5 equiv.) FC (Et0Ac) 78%
HOAt (2.5 equiv.) i-Pr2NEt (6.0 equiv.) 4 C, 3 h P
1 -,NoFt TEA, CH2Cl2 prep. HPLC c, Ex.83 H ll Ex.82 B.2 78% "
.3 o rt, 4 h method la cn .., ..
N,N-Dimethyl-..
N, n) , , ethylenediamine ..
i prep. HPLC 47% Ei') , Ex.84 '-N-^',---N-.. Ex.69 A.2 4 C, 1 h .
, , H method 3 ., Workup: Sat. aq. Na2CO3, Et0Ac =
Ex.85 Ø--.õ..---. 0 Ex A.2 1-(3-Aminopropyl)pyrro- prep. HPLC 57%
.69 lidine method la (TFA salt) Nir prep. HPLC
Ex.86 r I Ex.69 A.2 Azetidine method 3 80% id r) rN--prep. HPLC m ot Ex.87 0..,) Ex.69 A.2 Morpholine method 3 o c.4 ---.
o (1-Methyl-1H-imidazol-4- cA
prep. HPLC
27% t..1 c..4 Ex.88 H 1 i Ex.69 A.2 yl)methanamine N
method 1a (TEA salt) oo \ 4 C, 2 h and rt, 1 h , Starting General Purification 0 , No Rc Reagent Yield (isolated salt) k..) Material Proced.
Method cz )--, , c.4 --..

prep. HPLC
(...) ' -NH Naphthalen-2-.0 method 3 .0 ' Ex.89 so Ex.69 A.2 yInnethanamine and 73%
0 C, 3 h FC (Et0Ac) Table 16b: Examples of Core 04 (Ex.68-Ex.89; continued on the following page) P
r., gg Monoisotopic Rt (purity at No RC Formula [M+FI]E found LC-MS-Method .
Mass 220nm) N) , Ex.68-Ex.69: cf. experimental description , , Ex.70 NHCH3 C23H27N304 409.2 1.57 (96) 410.1 method la , Ex.71 NH2 C22H25N304 395.2 1.53 (95) 396.1 method 1a Ex.72 NHPh C28H29N304 471.2 1.96 (92) 472.1 method la Ex.73 0 '-- C30H33N304 499.2 1.97 (99) 500.1 method la H
.N
-Ex.74 C33H33N304 535.2 2.11 (96) 536.2 method 1a 1,0 SO
cn _ Ex.75 -11--1 C28H30N404 486.2 1.40 (93) 487.1 method la 00 L=4 N
CP
=-, t=J
Ex.76'N 0 C30H33N304 499.2 1.99 (96) 500.1 method 1a tn ul c..4 o, Ex.77 ''N"---'*--- .' C25H31N305 453.2 1.60 (99) 454.1 method la ot H
, -Ex.78 'N'cF3 C24H26F3N304 477.2 1.82 (96) 478.0 method la H

, i Monoisotopic Rt (purity at No RC Formula [M+FI]- found LC-MS-Method I.) =
Mass 220nm) (.2) )--, (...) Ex.68-Ex.69: cf experimental description c7, Ex.79 --NA C25H29N304 435.2 1.71 (98) 436.1 method 1a .gD
-.1 H
f Ex.80 H C26H33N304 451.2 1.90 (98) 452.1 method 1a Ex.81-.N.,....,.....OH
C24H29N305 439.2 1.50 (91) 440.1 method 1a H
, , ' Ex.82 '-"-or C28H35N306 509.2 1.97 (95) 510.1 method 1a Ex.83 -..11.--..,,is,OH
C24H27N306 453.2 1.50 (98) 454.1 method 1a P
r., .3 I
.
, , Ex.84 ` -N-'\.-- N... C26H34N404 466.2 1.40 (99) 467.1 method 1a , ..
, H
N.) .
, =Thii.-10 ..
, Ex.85 C29H38N404 506.3 1.46 (99) 507.2 method 1a 8 , , , Ex.86 F T C25H29N304 435.2 1.63 (92) 436.1 method la .
rN--Ex.87 0) C26H31N305 465.2 1.64 (92) 466.1 method 1a Ex.88 NY C27H31N504 489.2 1.43 (99) 490.1 method 1a \
ici ._.
n NH

Ex.89 Os/ C33H33N304 535.2 2.14 (93) 536.1 method 1 a ..o k.) 1-, c..) , (A
, ul (.4 cA
oo I
, , , , , , J Table 16c: Examples of Core 04 (Ex.68-Ex.89; continued on the following pages) 0 r.) No RC IUPAC
name (.4 .--w benzyl (9S,14S)-9,15-dimethy1-11,16-dioxo-7-oxa-10,15-diazatricyclo[15.3.1.12,9docosa- ,o c, Ex.68 OCH2Ph -.., 1(21),2(22),3,5,17,19-hexaene-14-carboxylate (9 S,14 S)-9,15-dimethy1-11,16-dioxo-7-oxa-10,15-d iazatricyclo[15.3.1.12,6]docosa-, Ex.69 OH
1(21),2(22),3,5,17,19-hexaene-14-carboxylic acid (9S,14S)-N,9,15-trimethy1-11,16-dioxo-7-oxa-10,15-diazatricyclo{1 5.3.1.12,6]docosa-Ex.70 NHCH3 1(21),2(22),3,5,17,19-hexaene-14-carboxamide P
(9S,14S)-9,15-dimethy1-11,16-dioxo-7-oxa-10,15-diazatricyclo[15.3.1.12,6]docosa-.
Ex.71 NH2 ..."
, .
1(21),2(22),3,5,17,19-hexaene-14-carboxamide , , (9S,14S)-9,15-dimethy1-11,16-dioxo-N-pheny1-7-oxa-10,15-diazatricyclo[15.3.1.12,6]docosa- "
Ex.72 NHPh 1(21),2(22),3,5,17,19-hexaene-14-carboxamide 8 .
,, .
, , H (9S,14S)-9,15-dimethy1-11,16-dioxo-N-phenethy1-7-oxa-10,15-diazatricyclo[15.3.1.12,6]docosa- .
Ex.73 40 N..
1(21),2(22),3,5,17,19-hexaene-14-carboxamide H
-N (9S,14S)-9,15-dimethyl-N-(1-naphthylmethyl)-11,16-dioxo-7-oxa-10,15-' Ex.74 so diazatricyclo[15.3.1.12,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide Ex.75 =ri.---n (9S,14S)-9,15-dimethy1-11,16-dioxo-N-(3-pyridinylmethyl)-7-oxa-10,15- id r) N diazatricyclo[15.3.1.12,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide ei -H
. (9S,14S)-9,15-dimethy1-11,16-dioxo-N-[(1S)-1-phenylethy1]-7-oxa-10,15- kµ.) o Ex.76 ,¨

'N IP diazatricyclo[15.3.1.12,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide w , o u, (9 S,14 S)-N-(2-methoxyethyl)-9,15-d 'methyl-11,16-d ioxo-7-oxa-10,15-w Ex.77 =.N.--..,0, cT
Ot H
diazatricyclo[15.3.1.12,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide No Re IUPAC
name N 1 I (9S,14S)-9,15-dimethy1-11,16-dioxo-N-(2,2,2-trifluoroethyl)-7-oxa-10,15-f...4 Ex.78 .-1\r'CF3 H
0-, c...) diazatricyclo[l 5.3.1.12,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide a, --.) , .1\ (9S,14S)-N-cyclopropy1-9,15-dimethy1-11,16-dioxo-7-oxa-10,15-Ex.79 'N
H diazatricyclo[15.3.1.12,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide -.N.-^.õ=-= (9 S,14S)-N-isobuty1-9,15-d imethy1-11,16-dioxo-7-oxa-10,15-d iazatricyclo[15.3.1.12,6]docosa-, Ex.80 H
1(21),2(22),3,5,17,19-hexaene-14-carboxamide Ex.81 (9S,14S)-N-(2-hydroxyethyl)-9,15-d 'methyl-11,16-d ioxo-7-oxa-10,15--.NI OH
p H
diazatricyclo[15.3.1.12,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide .
"
.3 ..Nyo ,14,. tert-butyl 2-([[(9S,14S)-9,15-dimethy1-11,16-dioxo-7-oxa-10,15-diazatricyclop 5.3.1.12,6]docosa- , Ex.82 g o 1(21),2(22),3,5,17,19-hexaen-14-yl]carbonyllamino)acetate "
n) , n) .
, .---.õ{OH 2-([[(9S,14S)-9,15-dimethy1-11,16-dioxo-7-oxa-10,15-diazatricyclo[15.3.1.12,6]docosa- o Ex.83 I" 8.7 , 1(21),2(22),3,5,17,19-hexaen-14-ylicarbonyl}amino)acetic acid .
' I, (9 S,14S)-N-[2-(dimethylamino)ethyl]-9,15-dimethy1-11,16-dioxo-7-oxa-10,15-1 Ex.84 1 H diazatricyclo[15.3.1.12,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide I

Ex.85 -..N..õ-...-\ (9 S,14S)-9,15-d i methy1-11,16-di oxo-N-[3-(1-pyrrol idinyl)propy1]-7-oxa-10,15-H
1.-"j d iazatricyclo[15.3.1 .1 2,6]d ocosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide )1t e==
N.' (9S,14S)-14-(1-azetanylcarbony1)-9,15-dimethy1-7-oxa-10,15-diazatricyclo[15.3.1.12,6]docosa-Ex.86 t 1 1(21),2(22),3,5,17,19-hexaene-11,16-dione ,-, r----''N' - (9 S,14S)-9,15-dimethy1-14-(morpholinocarbony1)-7-oxa-10,15-diazatricyclo[15.3.1.12,6]docosa- (..J
1 Ex.87 ' 1 6,) 1(21),2(22),3,5,17,19-hexaene-11,16-dione c..) u.

e...4 c, oo , , No RC
IUPAC name L.) I-, ' Ex.88 MiriN, (9S,14S)-9,15-dimethyl-N-[(1-methyl-1H-imidazol-4-yl)methyl]-11,16-dioxo-7-oxa-10,15- w ,¨
w N = =
\ dlazatncyclo[l 5.3.1.12,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide c, -.., ..-NH (9S,14S)-9,15-dimethyl-N-(2-naphthylmethyl)-11,16-dioxo-7-oxa-10,15-Ex.89 imo diazatricyclo[15.3.1.12,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide , Table 17a: Examples of Core 05 (Ex.90-Ex.114 and Ex.341-Ex.358; continued on the following pages) P
.
Starting General "
No RB RD Reagent Purification Method Yield (isolated salt) , Material Procedure .
"
Ex.90-Ex.92 cf. experimental description iv 0 , r..) .
, HCI-dioxane prep. HPLC
Ex.93 NH2 H Ex.90 B.1 1) 17% (TFA salt) ' , rt, 16 h method 1c ., o , Formaldehyde Ex.94 CH3 Ex.91 A.6.2 ; 5) FC (CH2C12/Me0H) 84%
H (36.5% in H20) HCI-dioxane Ex.95 NH2 CH3 Ex.94 B.1; 5) crude product quant. (HCI salt) rt, 2 h FC (CH2C12/Me0H) ,t r) Ex.96 =. so CH3 Ex.95 A.1.1; 5) 2-Naphthaleneacetic and prep. HPLC
41% (TFA salt) H acid ti method lb r.) o ca --o Ex.97 -,Nrk04 F , -- 40 Ex.91 A.6.3; 5) 3-Fluorobenzaldehyde FC
(CH2C12/Me0H) 80 /0 urk ul H
ca c7N
oo , Starting General No Ra RD Reagent Purification Method Yield (isolated salt) Material Procedure o w dioxane 1--, c..) Ex.98 NH2 õ Ex.97 BA; 5) crude product 95% (HCI salt) \.0 rt, 2 h --.1 Acetyl chloride prep. HPLC
Ex.99 NHCOCH3 CH3 Ex.95 A.1.2.1 61% (TFA salt) (4.0 equiv. in total) method la F
Ex.100 NHCOCH3 - 40 Ex.98 A.1.2.1; Acetyl chloride prep. HPLC 5) 64% (TFA salt) (4.0 equiv. in total) method la 1-Naphthaleneacetic prep. HPLC
Ex.101 0 0 ' 'N lel CH3 Ex.95 A.1.3; 5) acid method la 49% (TFA salt) P
N) .3 Ex.102 - NIN = CH3 Ex.95 A.3 Phenyl isocyanate prep. HPLC
57% (TFA salt) .., - H H rt, 15 h method la .
N) M
.
, Benzenesulfonyl iv .
N) , .
0, o chloride , , =
s dis,h prep. HPLC cn Ex.103 ' N - qui CH3 Ex.95 A.5; 5) (2.0 equiv.) 44% (TFA salt) H
method la Et3N (3.0 equiv.) 1 i-Pr2NEt (3.0 equiv.) , 2-(Dimethylamino)-o Ex.104 -, NA0J \--..õ 0 j IlA, Ex.91 A.1.3 acetic acid FC (CH2C12/Me0H) 83%
H
Id rt, 2 h n ,--3 m dioxane ot Ex.105 NH2 õLI\I Ex.104 B.1 rt, 2 h crude product 90% IN) )--, C..) --..

2-Phenylacetic acid vt ul ,, o op 9 1 prep. HPLC
Ex.106 Ex.105 A.1.3 (4.8 equiv.) method ca 41% (TFA salt) c, N , IL,-H
la rt, 40 h Starting General No RB RD Reagent Purification Method Yield (isolated salt) r..) Material Procedure I¨

_ c.4 , 1¨

Cyclopropanesulfonyl w .0 C.' 0, ,0 chloride -...) Ex.105 prep. HPLC
Ex.107 = 0 1 -}N, õLN A.5 (3.0 equiv.) method 1a 32% (TFA salt) Et3N (8.0 equiv.) rt, 16 h N-Succinimidyl N-Omethylcarbamate N
1 Ex.108 , AN
Ex.105 A.3 (1.4 equiv.) prep. HPLC
55% (TFA salt) P
' õi=cõ,N.., method la .
r., ' H H i-Pr2NEt (5.0 equiv.) .3 -, rt, 16 h .
N) m .
Cyclopropanesulfonyl chloride ' i o 00 1 Ex.109 = --11, \\ //
.S.õ\/ Ex.91 A.5 (5.2 equiv.) FC (CH2C12/Me0H) 64%
11 01- - Et3N (5.0 equiv.), i DMAP (0.1 equiv.) 45 C,48 h \\ ii HCI-dioxane quant.
Ex.110 NH2 ,S.,,, , Ex.109 B.1 crude product *d e) - V rt, 3 h (HCI salt) m 1 Benzoyl chloride t IN) o (2.0 equiv) prep. HPLC w Ex.111 ''N 0 ....s..., , Ex.110 A.1.2.1 19% (TFA salt) ¨.
H
V i-Pr2NEt (5.0 equiv.) method la CA
CA
Cw) C.' rt, 16 h co i Starting General No RB RD Reagent Purification Method Yield (isolated salt) w 1 Material Procedure c, ,-, r..4 ,-_ N-Succinimidyl N-...
f....) c"
o 0 methylcarbannate -...1 Ex.112 N..-11,0 H -AN Ex.91 A.3 (1.4 equiv.) FC (CH2C12/Me0H) 82%
H i-Pr2NEt (5.0 equiv.) rt, 16 h Ex.113 NH2 .....11,..N.- Ex.112 B.1 HCI-dioxane crude product quant.
rt, 4 h (HCI salt) H
P
o 0 3-Fluorobenzoyl N) .3 Ex.114 -Th 0 F N
IL. Ex.113 A.1.2.1 chloride prep. HPLC
method la 5% (TFA salt) .., l0 0.
H (4.0 equiv. in total) Iv . , Iv .
1-Naphthaleneacetic prep. HPLC method .4. , 040 , , F

Ex.341 ''N Ilit lel Ex.98 A.1.3 acid 1a and FC
47%
, i-Pr2NEt (9 equiv.) (CH2C12/Me0H) 2- Naphthaleneacetic prep. HPLC method I

Ex.342 -- Alb F
l SOO ir Ex.98 A.1.3 acid 1a and FC 34%
H
i-Pr2NEt (9 equiv.) (CH2C12/Me0H) ]
prep. HPLC method )-d F
n Ex.343 --NIN O. -- 0 Ex.98 A.3 2-Naphthylisocyanate 1a and FC 63% )-e H H i-Pr2NEt (5 equiv.) (CH2C12/Me0H) it t..) Naphthalene-2-sulfonyl c..4 -._ 0, õo F
prep. HPLC method 1 Ex.344 'N'ss' O. --40 Ex.98 A.5 chloride 1a 41% (TEA salt) CA
CA
Co) o., i-Pr2NEt (5 equiv.) oo I

, Starting General No RB RD Reagent Purification Method Yield (isolated salt) r.4 Material Procedure )..., .
t.4 2- Naphthalene-1--, (..) Ex.345 ..0 00 '' 0 F
Ex.98 A.1.3 propanoic acid prep. HPLC method Naphthalene-C.' 40% (TFA salt) , -.) la i-PrzNEt (9 equiv.) , Ex.346 Ex A.1.3 Avh F
3-Phenylpropionic acid prep. HPLC method ..-, .H 1110 lir .98 i-PrzNEt (9 equiv.) la 37% (TFA salt) o 1 F N, N-Dimethylglycine prep. HPLC method P
Ex.347 -µ11)=N -- io Ex.98 A.1.3 9% (TFA salt) .
H i-PrzNEt (9 equiv.) 1a , .
.
2- Naphthaleneacetic .
r., Ex.348 - 0 ' 00 '.N10 N H 0 Ex.92 A.1.3 acid FC (CH2C12/Me0H) 80% rv .
H
cn , . i-PrzNEt (6 equiv.) 47 , cn Ex.349 - 0 00 'IV H Ex.348 B.3 Hz, Pd(OH)2-C, Me0H crude product 97%
H
, o prep. HPLC method Ex.350 , 0 00 _...
'N F
It Ex.349 A.1.3 3-Fluorobenzoic acid 55% (TFA salt) H
1 a , 01 n P-i , m Benzaldehyde bc, Ex.351 --. 0 00 - 101 N Ex.349 A.6.3 Workup : CH2C12, sat. prep. HPLC method 51% (TFA salt) L.) c) ).., (.4 H
la aq. Na2CO3soln tit vi I
(...) C.' oo , 1 Starting General , No RB RD Reagent Purification Method Yield (isolated salt) l,) i Material Procedure 1¨

(..4 Ex.3520 le Ex.349 A.6.3 Phenylacetaldehyde Workup : CH2Cl2, sat.
prep. HPLC method 37% (TFA salt) c..4 C.' ct, --.1 H
la aq. Na2003soln , 3-Phenylpropion-, aldehyde prep. HPLC method , Ex.353 0 SOO -- *I Ex.349 A.6.3 30% (TFA salt) , H Workup :
CH2Cl2, sat. 1a I aq.
Na2003soln ;
P
Isovaleraldehyde (1.7 .
, r.) .3 Ex.354 o equiv.) prep. HPLC method .
, 0110 Ex.349 A.6.3 32% (TFA salt) .., ..
H Workup :
CH2Cl2, sat. la ..
N) rv .
aq. Na2003soln iv ..
cr) , .
lsobutyraldehyde , Ex.355 - c'' 400 'N Ex.349 A.6.3 Workup :
CH2Cl2, sat. prep. HPLC method 68% (TFA salt) .
, H ' s ./..'.N",.
1 a 1 aq.
Na2003soln 2-Dimethylaminoethyl-Ex.356 -'VI (3 0110 1 I, II Ex 349 2) FC (CH2C12/Me0H) 21%
,- 0-----.....,- -. =
chlorid hydrochloride prep. HPLC method n i=
Ex.357 , 0 00 I
N Ex.349 3) 2-Dimethylaminoethyl-2a and FC
17% R
=N ,-"-----.,.. chlorid hydrochloride 164 o (CH2C12/Me0H) --, c..) e cti 3,3-Dimethylbutyryl (.4 Ex.358 --N)-/< OH) Ex.95 4) FC (CH2C12/Me0H) 83% a, oe , H chloride 1) Ex.93 was obtained as a side product upon treatment of Ex.90 with HCI-dioxane; see description of synthesis of Ex.92-2-Dimethylaminoethylchloride hydrochloride (13 mg, 0.089 mmol) was added to a mixture of Ex.349 (50 mg, 0.089 mmol) and dry K2CO3 (61 mg, µ.z 0.44 mmol) in DCE (0.5 mL). The mixture was stirred at 50 C for 16 h. More 2-dinnethylaminoethylchloride hydrochloride (6.4 mg, 0.044 mmol) was added and stirring at 50 C continued for 2 h. Aqueous workup (CH2Cl2, sat.
aq. Na2CO3 soln; Na2SO4) and FC (CH2C12/Me0H 100:0 to 80:20) afforded Ex.356 (13 mg, 21%).
2-Dinnethylaminoethylchloride hydrochloride (64 mg, 0.44 mmol) was added to a mixture of Ex.349 (60 mg, 0.106 mmol) and i-Pr2NEt (0.121 mL;
0.71 mmol) in DMF (1 mL). The mixture was stirred at 50 C for 3 d. More 2-dimethylaminoethylchloride hydrochloride (64 mg, 0.44 mmol) and i-Pr2NEt (0.121 mL; 0.71 mmol) were added and stirring at 50 C was continued for 1 d. Aqueous workup (Et0Ac, sat. aq. Na2003 soln; Na2SO4) and FC (CH2C12/Me0H(conc. aq. NH3 soln 100:0:0.1 to 90:10:0.1) afforded Ex.357 (12 mg, 17%).
4) Synthesis of Ex.358 3,3-Dimethylbutyryl chloride (0.019 mL, 0.14 mmol) was added at 0 C to a suspension of Ex.95 (60 mg, 0.116 mmol) and pyridine (0.047 mL, 0.58 mmol) in CH2Cl2 (1.2 mL). The mixture was stirred at rt for 1 h and cooled to 0 C. Then i-Pr2NEt (0.059 mL; 0.35 mmol) and 3,3-dimethylbutyryl N
chloride (0.019 mL, 0.14 mmol) were added. The resulting clear soln was stirred for 30 min. Me0H (0.01 mL) was added and stirring continued for 10 min. The volatiles were evaporated. FC (CH2C12/Me0H 100:0 to 95:5) afforded Ex.358 ( 49 mg, 83%).
Data of Ex.358: cf. Table 17b 1H-NMR (DMSO-d6): 9.62 (br. s, 1 H); 9.22 (t, J ca. 1.9, 1 H); 9.18 (d, J =
2.0, 1 H); 8.93 (d, J =. 1.9, 1 H); 8.40 (br.s, 1 H); 8.08 (d, J = 6.5, 1 H);
7.59 (d, J = 7.6, 1 H); 7.40 (t, J = 7.9, 1 H); 6.82 (dd; J = 2.0, 8.3, 1 H);
4.53 - 4.41 (br. not resolved m, 3 H); 3.91 (t, J = 11.2, 1 H); 3.72 (dd; J =
7.0, 9.7, 1 H); 3.46 (d, J = 17.6, 1 H); 3.38 - 3.24 (m, 3 H, partially superimposed by H20 signal); 3.13 (dd-like m, 1 H); 2.62 (m, 2 H); 2.37 (s, 3 H); 2.14 (m, 1 H); 1.96 (s, 2 H); 1.93 (m, 1 H); 0.96 (s, 9 H).
5) Cf. experimental description for detailed procedure tt oo il I
Table 17b: Examples of Core 05 (Ex.90-Ex.114 and Ex.341-Ex.358; continued on the following pages) 0 t.J
' o , Monoisotopic Rt (purity at [M+Hp- w No RB RD Formula LC-MS-Method , ,-, Co4 Mass 220nm) found -.1 Ex.90-Ex.92: cf experimental description Ex.93 NH2 H C21H25N503 395.2 0.89 (97) 396.1 method la Ex.94 o - )-1., ---, CH3 C27H35N505 509.3 1.49 (97) 510.1 method la H
Ex.95 NH2 CH3 C22H27N503 409.2 1.43 (98) 410.1 method 2c _ P
Ex.96 . 0 00 'N CH3 C34H35N504 577.3 1.59 (99) 578.1 method la .
N, H
cm 0 Ail .
,J
Ex.97 - ,JJ.
F

603.3 2.44 (95) 604.0 method 2d .
' ' N OT
H
"
o Ex.98 NH2 F C28H30FN503 503.2 1.31 (90) 504.2 method 1a tv co , , . Ex.99 NHCOCH3 CH3 024H29N504 451.2 1.10 (96) 452.2 method la F
Ex.100 NHCOCH3 - 01 C30H32FN504 545.2 1.47 (97) 546.2 method la i i Ex.101 , 0 577.3 1.59 (98) 578.2 method la Ti 40 Ex.102 ='NIN illt CH3 C29H32N604 528.2 1.44 (98) 529.2 method la *d )-o, ,o , tt = :s' Ex.103 'hi 140 CH3 C28H31N505S
549.2 1.43 (99) 550.1 method la oo It.1 , o --, (...) o -...
Ex.104 -,N-J-L.0*,. 0 1,-11 cz (A
C30H40N606 580.3 2.02 (96) 581.2 method 2d t.,1 , , 1.
(.4 cc Ex.105 NH2 ,..k.._,N,, C25H32N604 480.2 0.97 (95) 481.1 method la I
' I Monoisotopic Rt (purity at [M+I-11+ 0 i No RB RD Formula LC-MS-Method r.) I
--, Mass 220nm) found c..) --Ex.106 ,, . op 0 , ,.., C33H38N605 598.3 1.45 (98) 599.2 method 1a o, Ex.107- :S' -r, -/ õLN C28H36N606S
584.2 1.30 (95) 585.1 method 1a Ex.108 -'N.A.N.-- 0 J. 1 L....,,N,..s C27H35N705 537.3 1.17 (97) 538.2 method la H H --,, o 00 P
Ex.109 N)..0 \\ 4, S
- , C29H37N507S
599.2 1.87 (93) 600.1 method 1a 0 N) , .3 H
0, ,J
Ø

.
Ø
..S..,v C24H29N505S "
Ex.110 NH2 499.2 1.20 (91) 500.1 method la 0 , , rv .
N.) , cs) o 00 , , Ex.111 --N
,,,v, C31H33N506S
603.2 1.73 604.0 method 1a o 0 Ex.112-.11)1Ø-\-., C28H36N606 552.3 1.67 (94) 553.1 method la H

, Ex.113 NH2 ,-1{-..N.- C23H28N604 452.2 1.04 (89) 453.1 method la , e) H
til o 0 ot ,o 1.1 .

1 Ex.114 -1 F C30H31FN605 574.2 1.63 (95) 575.2 method la JI

'I\ I 0 Ex.341 = .. 0 F
cm co) 671.3 2.37 (97) 672.0 method 2c c, oo I

, No RB RD Formula Monoisotopic Rt (purity at [M+1-1]+ LC-MS-Method k,.) o Mass 220nm) found c...) Ex.342 --: 400 -- 0 F
C40H38FN504 671.3 2.38 (94) 672.0 method 2c w H
===1 ' Ex.343 -NIN 400 '. 0 F
C39H37FN604 672.3 2.41 (96) 673.0 method 2c H H
I
1 d1 F
1 Ex.344 c...õ0 -- SP C38H36FN505S 693.2 2.42 (96) 694.0 method 2c ..ris 00 Ex.345 ,.kl WO - - 0 F
C41H40FN504 685.3 2.41 (97) 686.0 method 2c P
.
.
r., 0 ditb F
0, Ex.346 .
'N
III0 .- go- C37H38FN504 635.3 2.26 (97) 635.8 method 2c .
-, ..
H
u, al.

,Iv Ex.347 -,N)-1\1 -- 0 F C32H37FN604 588.3 2.01 (89) 588.5 method 2c m co , ..
, H

12-µ
Ex.348 -.NI o O. 'NJL 101 C41H39N506 697.3 2.06 (97) 698.0 method la .
H
Ex.349 0 00 H F C33H33N504 563.2 1.94 (88) 563.9 method 2c Ex.350 ..
H

1 mµt 00 , 0 C40H36FN505 685.3 1.97 (99) 686.0 method 1a H

Ex.351 0 400 - - 0 C40H39N504 653.3 2.38 (98) 654.0 method 2c ti n H
't N

f Ex.352 a 40101 -- Ai C41H41N504 667.3 2.40 (94) 667.9 method 2c w H
lir' 0 (11 Cli Wa "
Ex.353 4040 " 0 C42H43N504 681.3 2.51 (97) 682.1 method 2c o, ot, H

, , No RB RD Formula Monoisotopic Rt (purity at [M+Hp- LC-MS-Method 1.4 Mass 220nm) found (.4 , e-(.4 Ex.354''N 41116 C38H43N504 633.3 2.47 (98) 634.0 method 2c o, H
=,1 Ex.355 - O. C37H41N504 619.3 2.41 (96) 619.9 method 2c 11 '---"N
Ex.356 ' -N OP Z,0 Ni ,.. C38H42N606 678.3 2.05 (96) 679.3 method 2e H
Ex.357 0 410 I
N . ' C37H42N604 634.3 2.20 (96) 635.3 method 2e H ''',..,' *,..
C) .0 <
, Ex.358 _ N CH3 C28H37N504 507.3 1.43 (99) 508.2 method 1c P

N, ,J
Ø
t 1 J
.1=.
IV

Table 17c: Examples of Core 05 (Ex.90-Ex.114 and Ex.341-Ex.358; continued on the following pages) w .
, , , No RB RD
IUPAC name 1 - c it_ benzyl (9S,11R)-11-Rtert-butoxycarbonyl)amino]-14,20-dioxo-7-oxa-13,16,19,23-Ex.90''N 0 --''' -- I ' --0- tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaene-16-carboxylate H
Ex.91 tert-butyl N-[(9S,11R)-14,20-dioxo-7-oxa-13,16,19,23-NH'IL 0--1 H tetraazatetracyclor 9.3.1.12,6.09,13Thexacosa-1(25),2(26),3,5,21,23-hexaen-11-ylicarbamate NH2 benzyl (9 S,11R)-11-amino-14,20-dioxo-7-oxa-13,16,19,23- 'A
,-i Ex.92 m RP tetraazatetracyclo[l 9.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaene-16-carboxylate ot t4 I--, (9 S,11R)-11-amino-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-, Ex.93 NH2 H
ct' (A
1(25),2(26),3,5,21,23-hexaene-14,20-dione u, ON

I

, No RB RD
IUPAC name t.a o tert-butyl N-[(9S,11R)-16-methy1-14,20-dioxo-7-oxa-13,16,19,23-Ex.94 -.NYI.,T
CH',..-w H tetraazatetracycloM
9.3.1.126.09,13Thexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]carbamate \o o, \o (9S,11R)-11-amino-16-methy1-7-oxa-13,16,19,23-Ex.95 NH2 CH3 tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaene-14,20-dione N-[(9S,11R)-16-methy1-14,20-dioxo-7-oxa-13,16,19,23-Ex.96 0 4010 CH3 tetraazatetracyclo[19.3.1.1 2,6. 09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-y1]-2-(2-H
naphthyl)acetamide P
Aki F tert-butyl N-[(9S,11R)-16-(3-fluorobenzy1)-14,20-dioxo-7-oxa-13,16,19,23-rõ
Ex.97 N oT ' ' uip .3 ., , H
tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]carbamate .
rõ
õ 0 F (9S,11R)-11-amino-16-(3-fluorobenzy1)-7-oxa-13,16,19,23-Ex.98 NH2 (.0 , tetraazatetracyclo[l 9.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaene-14,20-dione i/
N-[(9S,11R)-16-methy1-14,20-dioxo-7-oxa-13,16,19,23-Ex.99 NHCOCH3 CH3 tetraazatetracyclo[l 9.3.1.126.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]acetamide õ 40 F N-[(9S,11R)-16-(3-fluorobenzy1)-14,20-dioxo-7-oxa-13,16,19,23-Ex.100 NHCOCH3 tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]acetamide N-[(9S,11R)-16-methy1-14,20-dioxo-7-oxa-13,16,19,23-0 ilb Ex.101 sIvi Igo CH3 tetraazatetracyclo[l 9.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-y1]-2-(1- ==kt e) ,--tt naphthyl)acetamide eo w co ,.., N-[(9S,11R)-16-methy1-14,20-dioxo-7-oxa-13,16,19,23-w ui Ex.102 ...N.-1-LN 411 CH3 tetraazatetracyclo[l 9.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-y1W- CJ1 H H
CA

phenylurea , No RB RD _ IUPAC name t.) o ,-.
N-[(9S,11R)-16-methy1-14,20-dioxo-7-oxa-13,16,19,23-f...
R, ,o ,-, w Ex.103 ''N's' 0 CH3 tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-c, H
v:
i -...1 , yl]benzenesulfonamide 1 (,:;i 0 1 tert-butyl N-[(9S,11R)-1642-(dimethylamino)acety1]-14,20-dioxo-7-oxa-13,16,19,23-Ex.104 - ,,,,),-.., _ , '11 - \ - -11\1', tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]carbamate 0 1 (9S,11R)-11-amino-1642-(dimethylamino)acety1]-7-oxa-13,16,19,23-Ex.105 NH2 ' -'r\l-, tetraazatetracyclo[19.3.1.12,6.09,13Thexacosa-1(25),2(26),3,5,21,23-hexaene-14,20-dione P
, N-R9S,11R)-1642-(dimethylamino)acety1]-14,20-dioxo-7-oxa-13,16,19,23-o "
.3 Ex.106 =10. __?1,N1,..
tetraazatetracyclo[19.3.1.12,6.09,13Thexacosa-1(25),2(26),3,5,21,23-hexaen-11-y1]-2- , 1 'NP
.
phenylacetamide "

tv co , , N-[(9S,-1642-(dimethylamino)acety11-14,20-dioxo-7-oxa-13,16,19,23-0, ,0 ' , Ex.107' \./ __IL...L..
tetraazatetracyclo[19.3.1.12,6.09,13Thexacosa-1(25),2(26),3,5,21,23-hexaen-11-ylicyclopropanesulfonamide 0 N-[(9 S,11R)-1642-(d imethylamino)acety1]-14,20-dioxo-7-oxa-13,16,19,23-Ex.108 - -it... ...- o I 26 913 tetraazatetracyclo[19.3.1.1 , .0 , ]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-y1]-1V-'N N .k.,,,N.,....
H H ' methylurea *o o 0 0 \,,,, ii, tert-butyl N-[(9S,11R)-16-(cyclopropylsulfony1)-14,20-dioxo-7-oxa-13,16,19,23- (-) )--i Ex.109 -- 'nr'll'o'-= - _s H
tetraazatetracycl o[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]carba mate 1.) (...) (9S,11R)-11-amino-16-(cyclopropylsulfony1)-7-oxa-13,16,19,23-, Ex.110 NH2 , - V
tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaene-14,20-dione c"
oo i , No RB RD
IUPAC name 0 r.) , o o 00 ii N-[(9S,-16-(cyclopropylsulfony1)-14,20-dioxo-7-oxa-13,16,19,23- w Ex.111 .
,-, w 1 -N 40 ,,S,...v tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-ylibenzamide o, --.1 tert-butyl N-[(9S,11R)-16-Kmethylamino)carbony1]-14,20-dioxo-7-oxa-13,16,19,23-Ex.112.. --'H - \ - N
tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]carbamate 0 (9S,11R)-11-amino-N-methy1-14,20-dioxo-7-oxa-13,16,19,23-Ex.113 NH2 , - -N' tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaene-16-H carboxamide P
0 0 (9 S,11R)-11-[(3-fluorobenzoyl)a minol-N-methyl-14,20-dioxo-7-oxa-13,16,19,23- "
, Ex.114 ''N IS F-11-.N.--tetraazatetracyclo[19.3.1.12,6.09,13Thexacosa-1(25),2(26),3,5,21,23-hexaene-16-.
H ..
o.
H
"
carboxamide iv , .1. .
N-[(9S,11R)-16-(3-fluorobenzy1)-14,20-dioxo-7-oxa-13,16,19,23-, , ' , 0 g rh Ex.341 --N we 0 F
tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-y1]-2-(1- , naphthyl)acetamide N-[(9S,11R)-16-(3-fluorobenzy1)-14,20-dioxo-7-oxa-13,16,19,23-Ex.342 -'N 00 40 F
tetraazatetracyclo[l 9.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-y1]-2-(2-H
naphthyl)acetamide r) N-[(9S,11R)-16-(3-fluorobenzy1)-14,20-dioxo-7-oxa-13,16,19,23-I .
M
i Ex.343 M,IIN 411. lip F
tetraazatetracyclo[19.3.1.12,6.09,13Thexacosa-1(25),2(26),3,5,21,23-hexaen-11-y1]-/V-(2- ot t4 H H

,-naphthyl)urea w e u, CA
c4 GA

No RB RD
IUPAC name r4 c) ,-, N-[(9S,11R)-16-(3-fluorobenzy1)-14,20-dioxo-7-oxa-13,16,19,23-c..4 ' N2S'filabdik 1., (...) Ex.344 -H WWI ' - 1101 F tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-y1]-2- µ.0 o, -..) naphthalenesulfonamide , N-[(9S,11R)-16-(3-fluorobenzy1)-14,20-dioxo-7-oxa-13,16,19,23-, Ex.345 --0 400 -- 0 F tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-y1]-3-(2-naphthyl)propanamide N-[(9S,-16-(3-fluorobenzy1)-14,20-dioxo-7-oxa-13,16,19,23-F
o P
Ex.346 --r, 0 0 tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-y1]-3- 0 rõ
.3 , phenylpropanamide .
o 1 Ex ,--46 F 2-(d imethyla mino)-N-R9 S,11R)-16-(3-fluorobenzy1)-14,20-dioxo-7-oxa-13,16,19,23- "
.347 ' , N ,,11,., N .., m , , H illri tetraazatetracyclo[19.3.1.12,13.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]acetamide i/
Ex.348 - 4101110 1,1V'0 benzyl (9 S,11R)-11-{[2-(2-naphthypacetyl]amino}-14,20-dioxo-7-oxa-13,16,19,23-.r1 H 110 tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaene-16-carboxylate Ex.349 --p,0 so H N-[(9S,11R)-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[1 9.3.1.12,6.09,13]hexacosa-H 1 (25),2(26),3,5,21,23-hexaen-11-y1]-2-(2-naphthyl)acetamide o N-[(9S,11R)-16-(3-fluorobenzoy1)-14,20-dioxo-7-oxa-13,16,19,23-ro Ex.350 -. cl OS -- 40 F tetraazatetracyclor 9.3.1.12,6.09,131hexacosa-1(25),2(26),3,5,21,23-hexaen-11-y11-2-(2- c-) ,-H
naphthyl)acetamide t o -N-[(9S,11R)-16-benzy1-14,20-dioxo-7-oxa-13,16,19,23-,--, (..4 , Ex.351 -. 001 - 0 tetra azatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-y1]-2-(2- o u, (..4 o, of) naphthyl)acetamide No RB RD IUPAC name N-[(9S,11R)-14,20-dioxo-16-phenethy1-7-oxa-13,16,19,23-Ex.352 -.N 0040 0 tetraazatetracyclo[l 9.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-y1]-2-(2-naphthyl)acetamide N-[(9S,11R)-14,20-dioxo-16-(3-phenylpropy1)-7-oxa-13,16,19,23-Ex.353 = 0 a. -Ipp tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-y1]-2-(2-Ti naphthyl)acetamide N-[(9S,11R)-16-isopenty1-14,20-dioxo-7-oxa-13,16,19,23-Ex.354 so tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-y1]-2-(2-naphthyl)acetamide N-[(9S,11R)-16-isobuty1-14,20-dioxo-7-oxa-13,16,19,23-o o.) C)Ex.355 op tetraazatetracyclo[19.3.1.12.6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-y1]-2-(2-naphthyl)acetamide 2-(dimethylamino)ethyl (9 S,11R)-11-{[2-(2-naphthypacetyl]amino}-14,20-dioxo-7-oxa-Ex.356 13,16,19,23-tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaene-16-carboxylate N-[(9 S,11 642-(dimethylamino)ethy1]-14,20-dioxo-7-oxa-13,16,19,23-0 abod-p Ex.357-env tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-y11-2-(2-naphthyl)acetamide 3,3-dimethyl-N-[(9S,11R)-16-methy1-14,20-dioxo-7-oxa-13,16,19,23-Ex.358 --N- Oft tetraazatetracyclo[19.3.1.12,0.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-oo ylibutanamide C
r..) c:.
Table 18a: Examples of Core 06 (Ex.115-Ex.128; continued on the following pages) c..4 , ,-, Starting General Purification w No RA Reagent Yield (isolated salt) c, Material Procedure Method i Ex.115-Ex.116: cf. experimental description prep. HPLC
method 3, then 0 1-NaP
hthaleneacetic acid Ex.117 ''IV it Ex.116 A.1.1 washed with Et20, 66%
H 0 C, 2 h then FC
P
(hexane/Et0Ac) .
r., -, prep. HPLC
.
, method 3, then "
.
i 0 Ex.118 op, Ex.116 A.1.1 2-Naphthaleneacetic acid washed with Et20, 60% n.) ._ N
H 0 C, 2 h then FC
(hexane/Et0Ac) 1-Pyrrolidineacetic acid 0 C, 2 h o Ex.119 EX.116 A.1.1 aq. workup (Et0Ac, sat. prep. HPLC
-'1\1)-1\rID 57%
H aq. NaHCO3 soln, H20, method 3 ot n sat. aq. NaCI soln;
,-Na2SO4) ..o r.) --, w ---o in w C,, ceo Starting General Purification No RA Reagent Yield (isolated salt) 1,4 ! Material Procedure Method ...
t.4 --Nicotinic acid w , 0 C, 2 h c, , 0 ;
Ex.120 Ex.116 A.1.1 aq. workup (Et0Ac, sat. prep. HPLC
s 72%
'N"-11"`"'""='', N
H ,J aq. NaHCO3 soln, H20, method 3 sat. aq. NaCI soln;
Na2SO4) 1 0 3-Methylbutanoyl chloride 1 Ex.121 -'N.A.. Ex.116 A.1.2 (1.2 equiv.) prep. HPLC
38%
P
Hmethod 3 "
.3 0 C, 2 h .
, ' Methyl chloroformate prep. HPLC
Ex.122 A.4 83%
-'NAO"- Ex.116 NI , H
0 C to rt, 2 h method 3 ca oo , , Cyclopropanesulfonyl , chloride (2.0 equiv.) 0, ,0 Et3N (3 equiv.) prep. HPLC
Ex.123 "-Ny:S',.v Ex.116 A.5 DMAP (0.1 equiv) 64%
H method 3 rt, 15 h *ri r) Workup: CHCI3, half-sat.
aq. NaHCO3 soln.;
"d Na o Na2S 04 1--, C=J

O ,0 Benzenesulfonyl chloride (41 prep. HPLC
c..) Ex -H= 0 Ex.116 A.5 (1.5 equiv.) 54%
at , method 3 rt, 1 h , i I
i i Starting General Purification 0 No RA Reagent Yield (isolated salt) 1,4 Material Procedure Method o ,...
c..e 1-, N-Succinimidyl N-c...) no k.z c, methylcarbamate -.) chromatography;
Ex.125 ',NN (1.8 equiv.)-- Ex.116 A.3 washing of crude 73%
i-Pr2NEt (4.5 equiv) H H
product with THF/CHC13 1:1 (0.9 mL) Et0H and Et20 rt, 16 h 2,5-Dioxopyrrolidin-1-y1 no P
pyridin-3-ylcarbamate .
N) chromatography;
.3 , .
o -----7)1 (13 equiv.) .
-, , .
Ex.126 Ex.116 A.3 washing of crude 70%
H H i-Pr2NEt (3 equiv) product with .
THF/CHCI3 1:1 (0.5 mL) N.) co , , Et0H and Et20 co .
rt, 15 h N
Isobutyraldehyde prep. HPLC
Ex.127 Ex.116 A.6.4 52%
H (1.05 equiv.) method 3 prep. HPLC
, method 3 3-Methylbutanal and 8%
Ex.128 '-N-\/\ Ex.116 A.6.4 ti H (1.05 equiv.) prep. HPLC (TFA salt) n method 1a m )-o r.) o )-, (..4 --o-ul ca o, co Table 18b: Examples of Core 06 (Ex.115-Ex.128; continued on the following page) 0 L.4 ,-µ
Monoisotopic Rt (purity at (.4 , No RA Formula [M-1-1-1]+ found LC-MS-Method 0-, (..) Mass 220nm) 1/44, -.1 Ex.115-Ex.116: of experimental description Ex.117 '=N lit C33H34N203S
WI 538.2 2.55 (95) 539.2 method 1a H
Ex.118 , 0 00 C33H34N203S 538.2 2.54 (95) 539.2 method 1a , 'N
H
, Ex.119 -'N,[1,,õ 0 C27H35N303S 481.2 1.82 (97) 482.2 method 1a P
H
N, 0, ,J
Ø
Ex.120 -'N'IN C27H29N303S 475.2 1.90 (92) 476.1 method la .
H .L......,,,..j "
iv Ø
-F.

Ex.121 -'N.--1-Lõ---.,.. C26H34N203S 454.2 2.32 (90) 455.2 method la , , i Ex.122 C23H28N204S 428.2 2.15 (97) 429.2 method la H
0, ,/0 = N 'S
Ex.123 - - -..v C24H30N204S2 474.2 2.23 (93) 475.1 method la H
e) Ex.124 sHs 0 C27H30N204S2 510.2 2.33 (82) 511.1 method la *re r.) c;
w , 0 vl u, Ex.125 --N)1...N..-- C23H29N303S 427.2 1.97 (88) 428.2 method 1a w c, , H H
co , , No RA Formula Monoisotopic Rt (purity at [M+H] found LC-MS-Method w =
Mass 220nm) )--, w 0 n ,.., Ex.126N = .1-LNr...- -. N C27H30N403S 490.2 1.80 (95) 491.2 method la c7, H H
N",/
Ex.127 C25H34N202S 426.2 1.97 (97) 427.2 method 1a H
Ex.128 --N-",./"=., C26H36N202S 440.2 2.05 (98) 441.2 method la ' H
P
.
"
.3 Table 18c: Examples of Core 06 (Ex.115-Ex.128; continued on the following page) .
, No RA IUPAC
name n) ,-allyl N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.02,7]tricosa-Ex.115 NHAlloc , , 1(23),2,4,6,19,21-hexaen-13-ylicarbamate (13 S,16R)-13-am ino-16-methyl-18-oxa-8-thia-15-azatricyclo[17.3.1.021tricosa-Ex.116 NH2 1(23),2,4,6,19,21-hexaen-14-one , 0 N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.021tricosa-' Ex.117 'N
H 40 1(23),2,4,6,19,21-hexaen-13-yI]-2-(1-naphthyl)acetamide , tJ
n Ex.118 . o 4* N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.021tricosa-m 'N 1(23),2,4,6,19,21-hexaen-13-yI]-2-(2-naphthyl)acetamide )1:1 r.) o ,-, N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.021tricosa-w Ex.119 s NLN
-....
c"
(A
H 1(23),2,4,6,19,21-hexaen-13-yI]-2-(1-pyrrolidinyl)acetamide u, w oo , , , , No RA IUPAC name 0k.4 o o JL
Ex.120 ./, N-[(I3S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.021tricosa w -.
,-, ''N" ----- ' N
w 4:>
H .,,.*,,..] 1(23),2,4,6,19,21-hexaen-13-ylinicotinamide c, -.1 o Ex.121 3-methyl-N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.02,1tricosa-''N
H 1(23),2,4,6,19,21-hexaen-13-yl]butanamide Ex.122 A methyl N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.021tricosa-'IV 0-.
H 1(23),2,4,6,19,21-hexaen-13-yl]carbamate N-[(I3S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.021tricosa-P
Ex.123 - N-S;,\ , .
'11 V 1(23),2,4,6,19,21-hexaen-13-yl]cyclopropanesulfonamide N) _., 0, ,0 -N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.027]tricosa-Ex.124 ' 'Ws' 101 0"
H
1(23),2,4,6,19,21-hexaen-13-yl]benzenesulfonamide n) , .4.
, IV

ri A N-methyl-Af-[(I3S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.02,1tricosa- .
Ex.125 H H 1(23),2,4,6,19,21-hexaen-13-yllurea yi n N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.024tricosa-Ex.126 H H 1 (23),2,4,6,19,21-hexaen-13-y1]-N-(3-pyridinyOurea (13 S,16R)-13-(isobutylamino)-16-methyl-18-oxa-8-thia-15-azatricyclo[17.3.1.021tricosa-Ex.127 ti H 1(23),2,4,6,19,21-hexaen-14-one n m (13S,16R)-13-(isopentylamino)-16-methyl-18-oxa-8-thia-15-azatricyclo[17.3.1.021tricosa- oc Ex.128 =
H 1(23),2,4,6,19,21-hexaen-14-one w ,-:-u, , w c, ot Table 19a: Examples of Core 07 (Ex.129-Ex.142; continued on the following pages) 0 w Starting General Purification No RA Reagent Yield (isolated salt) w --, Material Procedure Method c..) µ.0 c, Ex.129-Ex.130: cf. experimental description Naphthaleneacetic acid prep. HPLC
Ex.131 ''NI 14110 Ex.130 A.1.1 71%
H 0 C, 2 h method 3 Ex.132, 0 0401 Ex.130 A.1.1 2-Naphthaleneacetic acid prep. HPLC
73%

, H 0 C, 2 h method 3 1-Pyrrolidineacetic acid P
1 0 C, 2 h .
r., o-, aq. workup (Et0Ac, sat.
prep. HPLC ..
i .
Ex.133 -..N-1,,, 0 Ex.130 A.1.1 46% .
H aq. NaHCO3 soln, H20, method 3 "
.
..
41.
, sat. aq. NaCI soln;
cz .
, Na2SO4) , Nicotinic acid 0 C, 2 h aq. workup (Et0Ac, sat.
prep. HPLC
Ex.134 - ' N-A.."-----1 N
Ex.130 A.1.1 59%
H .1,...:),.... aq. NaHCO3 soln, H20, method 3 sat. aq. NaCI soln;
n Na2SO4) 0 3-Methylbutanoyl chloride od r.) 1 Ex.135 '' N Ex.130 A.1.2 (1.2 equiv.) prep. HPLC 77%
w I
method 3 ---=
H 0 C, 2 h (A
w c"
ot Starting General Purification 0 , No RA Reagent Yield (isolated salt) r..) , Material Procedure Method ,-, w ,.., Ex.136 N)I--0 Methyl chloroformate prep. HPLC w v:
--/"' Ex.130 A.4 H 0 C to rt, 2 h method 3 Cyclopropanesulfonyl chloride (1.5 equiv.) Et3N (3 equiv.) 1 0õ0 DMAP (0.1 equiv) prep. HPLC P
Ex.137 '-N-:S=vi Ex.130 A.5 71%
H CHCI3 (0.5 mL) method 3 .
N) -, rt, 15 h ..
..
Workup: CHCI3, half-sat.
N).
Ø
aq. NaHCO3 soln.;
.
, ,-Na2SO4 .

, ..Benzenesulfonyl chloride prep. HPLC
' 0 52%
Ex.138 hi Ex.130 A.5 (1.5 equiv.) method 3 N-Succinimidyl N-.
methylcarbamate ,t Ex.139 NAN Ex.130 A.3 (1.8 equiv.) prep. HPLC
r) . -..-49% 1-3 H H
i-Pr2NEt (4.5 equiv) method 3 iv 1,..) THF/CHCI3 1:1 (0.9 mL) o 1--, w rt, 20 h 'a CA
CA
G>
ON

, Starting General Purification 0 No RA
Reagent Yield (isolated salt) k..) Material Procedure Method ,-.
.
w I-2,5-Dioxopyrrolidin-1-y1 r.,4 e, pyridin-3-ylcarbamate -.4 o -5----ii (1.3 equiv.) prep. HPLC
Ex.140 =' A ..---,,N1 Ex.130 A.3 64%
11 11 i-Pr2NEt (3 equiv) method 3 THF/CHCI3 1:1 (0.5 mL) rt, 15 h N
Isobutyraldehyde prep. HPLC
Ex.141 Ex.130 A.6.4 57% P
H (1.05 equiv.) method 3 .
.3 prep. HPLC
, .
method 3 c, 3-Methylbutanal and 11% iv , Ex.142 ' -N------------..
Ex.130 A.6.4 oi H (1.05 equiv.) prep. HPLC (TFA salt) ' , method la Table 19b: Examples of Core 07 (Ex.129-Ex.142; continued on the following page) )-d r) Monoisotopic Rt (purity at 0-3 No RA Formula [M+FI]- found LC-MS-Method Mass 220nm) ot r..) --, Ex.129-Ex.130: cf experimental description w cz o ra Ex.131 '-E1 Ts C33H34N205S 570.2 2.28 (91) 571.2 method 1a cit ul w ON

J

, ' , Monoisotopic Rt (purity at 0 No RA Formula [M+H] found LC-MS-Method r.4 Mass 220nm) c4, -., (.4 Ex.132 õ
N O. C33H34N205S
570.2 2.20 (97) 571.2 method 1a -....
.-, w µ.0 H

Ex.133 -'1\1õit,,,,0 C27H35N305S 513.2 1.55 (93) 514.2 method 1a H

Ex.134 -'1\1)1µ", N C27H29N305S
507.2 1.59 (99) 509.0 method 1a H .1õ....) Ex.135 -'N.-IL...õ---..õ C26H34N205S
486.2 1.92 (99) 487.2 method 1a P

.
i H

.
, Ex.136 -..N.11.Ø-- C23H28N206S
460.2 1.74 (99) 461.0 method la .

r., H
N.) .
,-0, ,0 -P.
cs) , =
N µS/ ' Ex.137 - - =-. C24H3ON206S2 506.2 1.84 (99) 507.1 method 1a ,-H v O ,o , os, Ex.138 'hi, 0 C27H30N206S2 542.2 2.02 (97) 543.1 method la Ex.139 --N..11.N.- C23H29N305S
459.2 1.61 (99) 460.1 method 1 a t$
H H
n -.i 0 n Ex.140= N),,N,--N C27H30N405S
522.2 1.53 (98) 523.2 method 1a tt *le N
=-+
(...) -Ex.141 'i\r--'''----- C25H34N204S
458.2 1.70 (99) 459.2 method 1a 7:i3 H
c.n vi w o, Ex.142 ''1\1 C26H36N204S
472.3 1.78 (85) 473.2 method la oo H

Table 19c: Examples of Core 07 (Ex.129-Ex.142; continued on the following page) 0 w ,-, No RA IUPAC
name w ,-, w allyl N-[(13S,16R)-16-methy1-8,8,14-trioxo-18-oxa-8A6-thia-15-azatricyclo[17.3.1.021tricosa-o, Ex.129 NHAlloc 1(23),2,4,6,19,21-hexaen-13-yl]carbamate (13 S,16R)-13-am ino-16-methy1-18-oxa-8A6-thia-15-azatricyclo[17.3.1.02,1tricosa-Ex.130 NH2 1(23),2,4,6,19,21-hexaene-8,8,14-trione o ilki N-[(13S,16R)-16-methy1-8,8,14-trioxo-18-oxa-8A6-thia-15-azatricyclo[17.3.1.02,7]tricosa-Ex.131 i '-11 101 1(23),2,4,6,19,21-hexaen-13-y1]-2-(1-naphthyl)acetamide i P
o 400 N-[(13S,16R)-16-methy1-8,8,14-trioxo-18-oxa-8A6-thia-15-azatricyclo[17.3.1.021tricosa- 2 Ex.132 õ
N a' 0, ,J
H
1(23),2,4,6,19,21-hexaen-13-y1]-2-(2-naphthyDacetamide .
N-{(l3S,16R)-16-methy1-8,8,14-trioxo-18-oxa-8A6-thia-15-azatricyclo[17.3.1.02,71tricosa- m 4 Ex.133 H
.1.
-NI
' ' 1(23),2,4,6,19,21-hexaen-13-y1]-2-(1-pyrrolidinyl)acetamide 0, o N-[(13S,16R)-16-methy1-8,8,14-trioxo-18-oxa-8A6-thia-15-azatricyclo[17.3.1.021tricosa-Ex.134 H j 1(23),2,4,6,19 ,21-hexaen-13-yl]nicotinamide 0 3-methyl-N-[(I3S,16R)-16-methy1-8,8,14-trioxo-18-oxa-8A6-thia-15-Ex 135 ' 'NI
H azatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]butanamide n , II
-NH) methyl N-[(13S,16R)-16-methy1-8,8,14-triox o-18-oxa-8A6-thia-15-azatricyclo[17.3.1.021tricosa Ex.136 ..,.
0õ 1(23),2,4,6,19,21-hexaen-13-yl]carbamate r.>
cz ,--, N-[(13S,16R)-16-methy1-8,8,14-trioxo-18-oxa-8A6-thia-15-azatricyclo[17.3.1.021tricosa- w , Ex.137 - .S;,,, , , cz u, '11 V 1(23),2,4,6,19,21-hexaen-13-yl]cyclopropanesulfonamide LA
w 47, No RA IUPAC
name 0r..) , ...., , N-[(13S,16R)-16-methy1-8,8,14-trioxo-

18-oxa-8A6-thia-15-azatricyclo[17.3.1.021tricosa- f.,4 Ex.138 sH 0 1(23),2,4,6,19,21-hexaen-13-yl]benzenesulfonamide ,-, (...) µ.0 --.) Ex.139 -' N..k..N--- N-methyl-N-[(13S,16R)-16-methy1-8,8,14-trioxo-18-oxa-8A6-thia-15-H H azatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]urea ?I---""-- N-[(13S,16R)-16-methy1-8,8,14-trioxo-18-oxa-8A6-thia-15-azatricyclo[17.3.1.021tricosa-Ex.140 ''11---'N"----N
H H 1(23),2,4,6,19,21-hexaen-13-yll-N-(3-pyridinyl)urea Ex.141 N(13 S,16R)-13-(isobutylam ino)-16-methy1-18-oxa-8A6-thia-15-azatricyclo[17.3.1.021tricosa- P
H
"
1(23),2,4,6,19,21-hexaene-8,8,14-trione (13 S,16R)-13-(isopentylamino)-16-methy1-18-oxa-8A6-thia-15-azatricyclo[17.3.1.02,1tricosa- .
Ex.142 - ,N....--...õ..-.,. "
H 1(23),2,4,6,19,21-hexaene-8,8,14-trione m .4.
, , co iL
Table 20a: Examples of Core 08 (Ex.143- Ex.167; continued on the following pages) Starting General Purification No RA Reagent Yield (isolated salt) Material Procedure Method Ex.143-Ex.144: cf experimental description hl n Formaldehyde prep. HPLC 1-Ex.145 N(CH3)2 Ex.144 A.6.1 92%
(36% in H20) method 3 ts.) (:) 1-.
w Ex.146 - 'N------- Ex.144 A.6.4 Isobutyraldehyde prep. HPLC 16% -...
, H
method3 (A
, ul c.) , c2., iii6 F
prep. HPLC oo , Ex.147 N
'sH Rip, Ex.144 A.6.4 3-Fluorobenzaldehyde 46%
method 3 Starting General Purification 0 No RA Reagent Yield (isolated salt) r.) Material Procedure Method 4"
--, f...) , 1-, 0 Acetic anhydrid w cA
Ex.148 ''N'IL- prep. HPLC Ex.144 A.1.2 (2.2 equiv.) 94% (TEA salt) -.4 method la i H Pyridine (7 equiv.); rt _ , Methoxyacetic acid prep. HPLC
, Ex.149 = 'N j-L.,.,,O.õ.. Ex.144 A.1.11) 62%
H i-Pr2NEt (5 equiv.) method 3 2-(Dimethylamino)acetic acid Q
,1\1,11,,,N.., Ex.144 prep. HPLC
Ex.150 A.1.3 i-Pr2NEt (6 equiv.) method 3 H
.., Workup: CHCI3, .
10M aq NaOH soln "
.
N.) , -P, , Nicotinic acid cr) ' , -Pr2NEt (5 equiv.) prep. HPLC .
Ex.151 s'NA-----N Ex.144 A.1.1 i 68%
H .,...j. Workup: CHCI3, method 3 10M aq NaOH soln lsovaleric acid prep. HPLC
Ex.152 .-'N.1..õ---....... Ex.144 A.1.11) 15%
H i-Pr2NEt (5 equiv.) method 3 N-Boc-6-alanine prep. HPLC e) Ex.153 .-NIL--N10j< Ex.144 A.1.11) 88% ,=-i H H i-Pr2NEt (5 equiv.) method 3 m Iv o TEA, CH2Cl2 b.) Ex.154 -'1\1)H2 Ex.153 B.2 crude product 73% (TEA salt) f...) H rt, 2h -.
vi e...) C., , !
Starting General Purification 0 I No RA
Material Procedure Reagent Method Yield (isolated salt) r.) .:::.
=-, w 1¨
o w , , 1 1-Naphthaleneacetic acid prep. HPLC CA
Ex.155 õ
N Mb Ex.144 A.1.11) "PP I
i-Pr2NEt (5 equiv.) method 3 and FC 69% H --.1 (hexane/Et0Ac) Ex.156 Ex.144 A.1.11) ., 0 so 2-Naphthaleneacetic acid prep. HPLC
66%
N
H
i-Pr2NEt (5 equiv.) method 3 0 3,3,3-Trifluoropropionic Ex.157 -,N prep. HPLCcF3 Ex.144 A.1.11) acid 45%
method 3 P
H i-Pr2NEt (5 equiv.) .
r., ' o prep. HPLC .., ..
i 3-Fluorobenzoic acid ' ..
! Ex.158 - m F
N) i '11 0 Ex.144 A.1.11) method 3 and FC 44%
i-Pr2NEt (5 equiv.) m 0 , ..
(hexane/Et0Ac) o .
, 2,5-Dioxopyrrolidin-1-yi , o -1'71 pyridin-3-ylcarbamate prep. HPLC
Ex.159= A --,. N Ex.144 'NI r\ A.3 78%
H H
(1.3 equiv) method 3 , 1 i-Pr2NEt (5 equiv.) N-Succinimidyl-N-. 0 . methylcarbannamte (1.3 prep. HPLC
78%
, Ex160 oci , --NAN,- Ex.144 A.3 equiv.) method 3 n H H

m , i-Pr2NEt (5 equiv.) od r4 c, w (1) Ch f...) CA
CO

, , , , Starting General Purification 0 No RA Reagent Yield (isolated salt) 1,4 Material Procedure Method 1¨

c..4 tert.-Butyl 3-((2,5-c..J
, dioxopyrrolidin-1- v:

prep. HPLC
Ex.161 -N1N---)I-0-(Ex.144 A.3 yloxy)carbonylamino)prop 84%
H H method 3 anoate (1.3 equiv.) i-Pr2NEt (5 equiv.) TFA, CH2Cl2 Ex.162 -'1,11 ''''''.1 : )OH Ex.161 B.2 rt, 2h crude product 75% (TFA salt) H
P
Methanesulfonyl chloride ,D
,,, .3 0, ,0 (3 equiv.) , 1 - ,µS/
prep. HPLC -Ex.163 'N '''' Ex.144 A.5 DMAP (0.1 equiv.) 71%
H method 3 iv , NEt3 (5 equiv.) al .
, ,D
CHCI3, rt, 2 d ,2-7 Cyclopropanesulfonyl I
J 0, ,O
chloride (3 equiv.) prep. HPLC
Ex.164 '-N-'S'---v Ex.144 A.5 DMAP (0.1 equiv.) method la 55% (TFA salt) , H
NEt3 (5 equiv.) CHCI3, rt to 50 C,3 d ti Benzenesulfonyl chloride n ,-0, , o , , S' 0 Ex.144 A.5 (3 equiv.) prep. HPLC ot Ex.165 57% L.) NEt3 (5 equiv.) method 3 r..4 --.
CHCI3, rt, 2 d ul cn t..4 c\
Methyl chloroformate prep. HPLC oc Ex.166 - -.N .)1-.0-#. Ex.144 A.4 66%
H (0.89 equiv.); it, 2 h method 3 ' 1 Starting General Purification 0 ! No RA
Material Procedure Reagent Method Yield (isolated salt) L.) ,-, (.4 , , , 2-Methoxyethyl chloro- c..) prep. HPLC
= .a Ex.167 --NYL-0...--0,.. Ex.144 A.4 formate (0.96 equiv.); 52%
H
method 3 = rt, 2 h 1) Method A.1.1; modified aq. workup: The (reaction) mixture was distributed between CH2Cl2 and 1 M aq. HCI soln. The organic phase was dried (Na2SO4), filtered and concentrated.
, P
Table 20b: Examples of Core 08 (Ex.143-Ex.167; continued on the following pages) .
"
.3 , Monoisotopic Rt (purity at .
No RA Formula [M4-H] found LC-MS-Method .
Mass 220nm) "
n.) , ..
cm , Ex.143-Ex.144: cf. experimental description m .
, , Ex.145 N(CH3)2 C22H29N302S 399.2 1.35 (98) 400.1 method 1a .
NI
Ex.146 C24H33N302S 427.2 1.46 (95) 4282 method la H
Ex.147 40 F
C27H30FN302S 479.2 1.53 (95) 480.2 method la N
' - H

Ex.148 ' 'N'll'''' C22H27N303S 413.2 1.40 (99) 414.1 method 1a =11 H
n P-i , 0 m Ex.149 -'N)-0,, C23H29N304S 443.2 1.49 (94) 444.2 method 1a Iv r.) o H
=-, tA

-a v, vi Ex.150 -'N.-J1.õ..M.., C24H32N403S
456.2 1.94 (96) 457.2 method 2c r.,4 CA
H
co , , , , Monoisotopic Rt (purity at 0 No RA Formula [M+FI] found LC-MS-Method c.J
Mass 220nm) w )--, w Ex.151 ''N-..1C-N C26H28N403S 476.2 1.86 (92) 477.0 method 2c 0, H I

, Ex.152 ='N.,1L, C25H33N303S 455.2 1.66 (90) 456.2 method 1a H
Ex.153 -N-J 1-----N10-1< C28H38N405S 542.3 170(90) 543.2 method 1a H H
Ex.154 '-N151...------'NH2 C23H30N403S 442.2 1.30 (87) 443.2 methodic p H

. 0 illb m ,J
Ex.155 N WO C32H33N303S 539.2 1.91 (93) 540.1 method la .
H
Ø

Ex.156 , 0 400 C32H33N303S 539.2 1.90 (97) 540.1 method la N.) , .1\1 H
u, 12-µ

en Ex.157 -.N.1,-CF3 C23H26F3N303S 481.2 1.61 (96) 482.2 method 1a H

, F
Ex.158 -NH 0 C27H28FN303S 493.2 1.76 (99) 494.2 method 1a , 1 Ex.159 -,NIN 11 C26H29N503S
491.2 1.86 (90) 492.1 method 2c ti H

Ex.160 - 'NAN.-- C22H28N403S 428.2 1.39 (99) 429.1 method la Iv tsJ

H H
c.4 --.
c, Ex.161 -NIN-----10-J< C28H38N405S 542.3 2.13 (99) 543.1 method 2c vi vi CA
CT
GO
Ex.162 -'1,11V--JOH C24H30N405S 486.2 1.38 (98) 487.2 method la H H

I
, Monoisotopic Rt (purity at 0 No RA Formula [M+Fl] found LC-MS-Method w Mass 220nm) c' ,-, c..) , ,,s, c..) Ex.163 'N '-- C21H27N304S2 449.1 1.46 (99) 450.1 method 1a vz 47, H

0 ,o Ex.1 64 ' - N ..\ , C23H29N304S2 V 475.2 1.55 (99) 476.0 method 1a H
- "
Ex.165 'N'S 40 C26H29N304S2 511.2 1.72 (99) 512.1 method 1a P

.
I Ex.166 -.NAØ.., C22H27N304S 429.2 1.49 (99) 430.1 method 1a . 3 H.
r., Ex.167= N-11-).-...a. C24H31N305S 473.2 1.52 (99) 474.2 method la -P, Table 20c: Examples of Core 08 (Ex.143-Ex.167; continued on the following pages) No RA IUPAC
name ' allyl N-R1OR,13S)-10-methy1-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.021tricosa-Ex.143 NHAlloc it 1(23),2,4,6,19,21-hexaen-13-yl]carbamate n ,-(10R,13S)-13-amino-10-methy1-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.02,1tricosa-Ex.144 NH2 It w 1(23),2,4,6,19,21-hexaen-12-onetz ,.-c...) "a (10R,13S)-13-(dimethylamino)-10-methy1-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.02:1tricosa- th th Ex.145 N(CH3)2 c..4 e, 1(23),2,4,6,19,21-hexaen-12-one co , , , No RA IUPAC
name t,) o i w Ex.146 N(10R,13S)-13-(isobutylamino)-10-methy1-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.021tricosa , i)¨

H
c..4 1(23),2,4,6,19,21-hexaen-12-one o, vD
-..) Ex.147 N 0 F (10R,13S)-13-{(3-fluorobenzyl)amino]-10-methy1-8-oxa-18-thia-11,21-H
diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-12-one Ex.148 N-[(10R,13S)-10-methy1-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.021tricosa-, -11*--"-H 1(23),2,4,6,19,21-hexaen-13-yl]acetamide 2-methoxy-N-[(10R,13S)-10-methy1-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.021tricosa-Ex.149 ''I\IJL
P
.
H 1(23),2,4,6,19,21-hexaen-13-yl]acetamide "
, V I 2-(d imethylamino)-N-[(10R,13 S)-10-methy1-12-oxo-8-oxa-18-thia-11,21- ' Ex.150 ''1\1--"--"N"-IV

H diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yliacetamide iv , C.71 cn O.
N-[(10R,13S)-10-methy1-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.021tricosa- ' , , .
Ex.151 '1\1)"1 N
H j...,_,õ..õ,1 1(23),2,4,6,19,21-hexaen-13-yl]nicotinamide , , Ex.152 3-methyl-N-R1OR,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.021tricosa-'1\1 H 1(23),2,4,6,19,21-hexaen-13-yl]butanamide n L., tert-butyl N-(3-{[(10R,13S)-10-methy1-12-oxo-8-oxa-18-thia-11,21-Ex.153 --N''''''''' N".-'0"--'=
H
H't , diazatricyclo[17.3.1.02,71tricosa-1(23),2,4,6,19,21-hexaen-13-yl]amino}-3-oxopropyl)carbamate n )--3 , t 3-amino-N-[(10R,13S)-10-methy1-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.02,1tricosa-, Ex.154 -..N-1,---",N, w H ¶2 1(23),2,4,6,19,21-hexaen-13-yl]propanamide ,--w -,--:, 0 N-[(10R,13S)-10-methy1-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.021tricosa- (A
Ex.155 H el 1 (23),2,4,6,19,21-hexaen-13-y1]-2-(1-naphthyl)acetamide t...h w ,z oo I

, No RA IUPAC
name 0 t..) o , ,-, N-[(10R,13S)-10-methy1-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.021tricosa- (.4 Ex.156 = o (..1 "1 1(23),2,4,6,19,21-hexaen-13-y1]-2-(2-naphthyl)acetamide o, o -.., = .N,J1,_.,cF3 3,3,3-trifluoro-N-[(10R,13S)-10-methy1-12-oxo-8-oxa-18-thia-11,21-Ex.157 H diazatricyclo[17.3.1.02,1tricosa-1(23),2,4,6,19,21-hexaen-13-yl]propanamide o 3-fluoro-N-[(10R,13S)-10-methy1-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.021tricosa-Ex.158 - 0 F
mi 1(23),2,4,6,19,21-hexaen-13-yl]benzamide P
0, ,N -.' :7 ) N-[(10R,13 S)-10-methy1-12-oxo-8-oxa-18-thia-11,21-d iazatricyclo[l 7.3.1.021tricosa- .
Ex.159 - N
' ¨
n, N-1-L.
0, H H 1(23),2,4,6,19,21-hexaen-13-y1W-(3-pyridinyl)urea -J

.
Ex.160 - ,-11,,..- N-methyl-W-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.021tricosa-N.) N), I-' 0.
'1.1 11 1(23),2,4,6,19,21-hexaen-13-yljurea cy) , , , tert-butyl 34({[(10R,13S)-10-methy1-12-oxo-8-oxa-18-thia-11,21-.
Ex.161 --NIN---(-Lto- diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]aminolcarbonyl)amino]propanoate , , , 0 9 34({[(10R,13S)-10-methy1-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.021tricosa-Ex.162--NAN------'0H
1-, " 1(23),2,4,6,19,21-hexaen-13-yllaminolcarbonyl)amino]propanoic acid ori .'0 N-[(I0R,13S)-10-methy1-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.021tricosa 'NS-n Ex.163 =
m H 1(23),2,4,6,19,21-hexaen-13-yl]methanesulfonamide "t 1,4 o N-[(I0R,13S)-10-methy1-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.021tricosa- ,.., w cal Ex.164 - S' 'N ''\7 1(23),2,4,6,19,21-hexaen-13-yl]cyclopropanesulfonamide e--cA
ta 0 \
co , No RA IUPAC
name L=7 0, ,0 ==, c..4 N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.021tricosa-Ex.165 ''N' 0 ,-c..J
4:, H 1(23),2,4,6,19,21-hexaen-13-yl]benzenesulfonamide c"
.c, Ex.166 methyl N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.021tricosa-' ' N AO"-H 1(23),2,4,6,19,21-hexaen-13-yl]carbamate , (13LO'''''.'a"" 2-methoxyethyl N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21-, Ex.167 H
d iazatricycl o[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-ylicarbam ate P
.
N) .3 _., Table 21a: Examples of Core 09 (Ex.168-Ex.192; continued on the following pages) ,, .
r.) , Starting General Purification No RA Reagent Yield (isolated salt) -.4 .
-, Material Procedure Method , Ex.168-Ex.169 cf experimental description Formaldehyde prep. HPLC
Ex.170 N(CH3)2 Ex.169 A.6.1 67%
(36% in H20) method 3 prep. HPLC
Ex.171 N---.'..----=-= Ex.169 H A.6.4 Isobutyraldehyde 44%
method 3 od n F
prep. HPLC
Ex.172 HN 0 Ex.169 A.6.4 3-Fluorobenzaldehyde 57%
method 3 ot r.) 1-, '-'1\rj-L- Ex.169 A.1.2 Acetic anhydride prep. HPLC
79%
Ex.173 w vl (1.2 equiv.) method 3 CA
H
w o, oo Starting General Purification 0 No RA Reagent Yield (isolated salt) t..) Material Procedure Method o ,-, c..J
' 0 1¨
w Ex.174 -,N.-c,-0--, Ex.169 A.1.11) Methoxyacetic acid prep. HPLC 27 /0 method 3 (Dinnethylannino)acetic ,'N)L.......N..õ Ex.169 prep. HPLC
Ex.175 A.1.3 acid 9%
H method 3 Workup:CH2Cl2 O Nicotinic acid Ex.176 µ'NA------N Ex.169 A.1.1 Workup: CH2Cl2, sat .aq.
prep. HPLC 26%
1 H jJ Na2CO3 method 3 P
.
N) o 0 , , Ex.177 = 'N.A._...----,.õ Ex.169 A.1 prep. HPLC .11) Isovaleric acid 18% .
method 3 "
H

n.) , prep. HPLC
co .
Ex.178 'N-JcL----Nlo-( Ex.169 A.1.11) N-Boc-8-alanine 57% .
, , H H
method 3 .
o TFA, CH2Cl2 Ex.179 -, N )-Lõ,,,, N H2 Ex.178 B.2 rt, 2h crude product 41% (TFA salt) H

prep. HPLC
Ex.180 's N Ex.169 A.1.11) 1-Naphthaleneacetic acid 42%
H
method 3 Ex.181 Ex.169 A.1.11) 2-Naphthaleneacetic acid prep. HPLC
40%
id n 'N

H
method 3 O id t,..) Ex.182 ,,N,11,.,õ,cF3 Ex.169 A.1.11) 3,3,3-Trifluoropropionic acid prep. HPLC 22% )--, method 3 -...
H
col o u, Ex.183 -'IV III/ Ex.169 A.1.11) 3-Fluorobenzoic acid prep. HPLC
w F
58%
C., H
method 3 Starting General Purification 0 No RA Reagent Yield (isolated salt) w , Material Procedure Method c' 1¨

(...) --2,5-Dioxopyrrolidin-1-y1 ..., c...) , yi, -.7 ) prep. HPLC
<7, Ex.184 'N N"------' "N Ex.169 A.3 pyridin-3-ylcarbamate (1.3 73%
-.) H Hmethod 3 equiv.) , 0 N-Succinimidyl N-prep. HPLC
, Ex.185 -.N )(N.,- Ex.169 A.3 methylcarbamate (1.3 76%
' method 3 , H H
, equiv.) ]
tert.-Butyl 3-((2,5-, P
dioxopyrrolidin-1-prep. HPLC .
Ex.186 '-NIN-------1)1-0-k Ex.169 A.3 77% "
.3 H H
yloxy)carbonylamino)propan method 3 .
-, , .
oate (1.3 equiv.) tv , , Ex.187 '-NIN-------3-0H Ex.186 B.2 TEA, CH2Cl2 crude product 75% al .
, H H
CO o u, H
Methanesulfonyl chloride .
0, ,0 (2 equiv.) prep. HPLC
Ex.188 ''N''S/' Ex.169 A.5 DMAP (0.1 equiv.) 70%
H
method 3 Et3N (3 equiv.) CHCI3, rt, 2 d , , Cyclopropanesulfonyl 1-ri n 0, ,0 chloride oi \
prep. HPLC til Ex.189 '-N--S--..v' Ex.169 A.5 DMAP (0.1 equiv.) 53% 1-ci r.) H
method 3 c>
Et3N (3 equiv.) CHCI3, rt, 2 d tm c..) o, oo Starting General Purification 0 , No RA Reagent Yield (isolated salt) t,4 Material Procedure Method o ,.., e..) ..., -'hl,'S' 0 Ex.169 prep. HPLC o o, Ex.190 A.5 Benzenesulfonyl chloride 51% o ---.1 method 3 Methyl chloroformate (0.86 prep. HPLC
Ex.191 -.N.4Ø- Ex.169 A.4 52%
equiv); rt, 2 h method 3 H
2-Methoxyethyl chloro-prep. HPLC
Ex.192 = NX --^v ,. Ex.169 'H A.4 formate (0.97equiv); rt, 2 h method 3 55% P

r., , 1) Method A.1.1; modified aq. workup: The (reaction) mixture was distributed between CH2Cl2 and 1 M aq. HCI soln. The organic phase was dried .
N) (Na2SO4), filtered and concentrated.
o m , (3) , o .
iL
Table 21b: Examples of Core 09 (Ex.168-Ex.192; continued on the following pages) , Monoisotopic Rt (purity at No RA Formula [M+H]- found LC-MS-Method , Mass 220nm) Ex.168-Ex.169 of experimental description ,t Ex.170 N(CH3)2 C22H29N304S
431.2 1.39 (97) 432.1 method 1a r) )-i Ex 171 N----.N.---- C24H33N304S
H 459.2 1.53 (95) 460.1 method la )-ti Ls.) c) , F
.., Ex.172 'HN 40 C27H30FN304S
511.2 1.61 (96) 512.1 method 1a i..4 , o tm ut f....) Ex.173 ''N)L- C22H27N305S
445.2 1.50 (100) 446.1 method la cA
oo H

Monoisotopic Rt (purity at No RA Formula [M+1-1]+ found LC-MS-Method w Mass 220nm) o c.4 --, L.) Ex.174 -.N-1,,,.-0,, C23H29N306S 475.2 1.57 (96) 476.0 method 1a Ex.175 ,'N,..11õ.õ.N...õ C24H32N405S 488.2 1.38 (92) 489.1 method 1a H

Ex.176 -'N-J-IN C26H28N405S 508.2 1.43 (98) 508.9 method 1a H
-.,.....,:j , P
o .
, Ex.177 -'N.-it.,..õ--- C25H33N305S 487.2 1.77 (97) 488.2 method la .3 0, -., . H
..
..
Ex.178 -N-(-^N-11-0-k C28H38N407S 574.2 1.83 (98) 575.1 method 2c H H
o.
0) , c, Ex.179 ' 'N fil.."----"'N H2 C23H30N405S 474.2 1.35 (99) 475.2 method 1a ' , ,-, Ex.180 s'N1 lip C32H33N305S 571.2 2.03 (97) 572.0 method la H
Ex.181 õ
N 400 C32H33N305S 571.2 2.05 (100) 572.1 method la H

Ex.182 , 'NI)11,,CF3 C23H26F3N305S 513.2 1.74 (99) 514.1 method 1a n H
o , Ex.183 'N 0 F C27H28FN305S 525.2 1.90 (92) 526.1 method la ti I.) cD
La O' , n , u A
Ex.184 -,N-ko N,-:..,. N C26H29N505S 523.2 1.42 (99) 524.0 method 1a vt (4 c, H H
oo , , ' Monoisotopic Rt (purity at 0 No RA Formula [M+1-11+ found LC-MS-Method r.J
Mass 220nm) o --, w , w , Ex.185 -'1\1..-11-.N. C22H28N405S
460.2 1.48 (99) 461.0 method 1a \z, a, Na , H H
Ex.186 'NIN".....iLO'i< C28H38N407S
574.2 1.88 (98) 575.1 method 2o H H

, Ex.187--NI ---j C24H3ON407S 518.2 1.45 (97) 519.1 method la = ,µS/
' Ex.188 'NI C21H27N306S2 481.1 1.58 (99) 482.1 method la H
P
Ex.189 ',N,'S',\/ C23H29N306S2 507.1 1.68 (95) 508.0 method la -, H.
, ,,,s, N.) , Ex.190 Mil 10 C26H29N306S2 543.1 1.85 (96) 544.1 method la o) Iv , , , Ex.191 -.N..11-Ø,- C22H27N306S
461.2 1.60 (98) 462.1 method la H
Ex.192 ''N)(Dt'-a"---' '=- C24H31N307S
505.2 1.63 (99) 506.2 method 1a H

"d n )-3 Table 21c: Examples of Core 09 (Ex.168¨Ex.192; continued on the following pages) t., ,-, i w No RA
IUPAC name tm ally] N-R1OR,13S)-10-methyl-12,18,18-trioxo-8-oxa-18A6-thia-11,21-w o Ex.168 NHAlloc oo diazatricyclo[17.3.1.02,7]tricosa-1(23),2,4,6,19,21-hexaen-13-ylicarbamate No RA IUPAC
name 0k=J
o *.
(10R,13S)-13-amino-10-methy1-8-oxa-18A6-thia-11,21-diazatricyclo[17.3.1.021tricosa- w Ex.169 NH2 ,.., w 1(23),2,4,6,19,21-hexaene-12,18,18-trione ON
4:) --.1 ( 10 R,13S)-13-(d imethylamino)-10-methy1-8-oxa-18A6-thia-11,21-d iazatricycl o[17.3.1.02,1tricosa-Ex.170 N(CH3)2 1(23),2,4,6,19,21-hexaene-12,18,18-trione - -N ----...õ-- (10 R,13S)-13-(isobutylam ino)-10-methy1-8-oxa-18A6-thia-11,21-d iazatricycl o[17.3.1.021tricosa-1 Ex.171 H 1(23),2,4,6,19,21-hexaene-12,18,18-trione F (10R,13S)-13-[(3-fluorobenzypamino]-10-methyl-8-oxa-18A6-thia-11,21-I Ex.172 H
P
diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaene-12,18,18-trione ,, i 0 .3 , Ex.173 .. g N-[(10R,13S)-10-methy1-12,18,18-trioxo-8-oxa-18A6-thia-11,21-diazatricyclo[17.3.1.021tricosa- .
'IA ---'''' 1(23),2,4,6,19,21-hexaen-13-yllacetamide ,, H
o) , 6) .
2-methoxy-N-[(10R,13S)-10-methy1-12,18,18-trioxo-8-oxa-18A6-thia-11,21-.
, Ex.174 L
, H diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]acetamide jj 1 2-(dimethylamino)-N-[(10R,13S)-10-methy1-12,18,18-trioxo-8-oxa-18A6-thia-11,21-Ex.175 ''1\1.1\1 H diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]acetamide Ex.176 N-[(10R,13S)-10-methy1-12,18,18-trioxo-8-oxa-18A6-thia-11,21-diazatricyclo[17.3.1.021tricosa---1\1-JL-N
H
.J 1(23),2,4,6,19,21-hexaen-13-yl]nicotinamide hzi c-) iq Ex.1 s 3-methyl-N-R1 OR,13S)-10-methy1-12,18,18-trioxo-8-oxa-18A6-thia-11,21- m hl 'N
r.) H diazatricyclo[17.3.1.02,1tricosa-1(23),2,4,6,19,21-hexaen-13-yl]butanamide ,-, w --o-, ? L., tert-butyl N-(3-{[(10R,13S)-10-methy1-12,18,18-trioxo-8-oxa-18A6-thia-11,21- CJ1 Ex.178 -N-------- N-----0----w H H diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]amino}-3-oxopropyl)carbamate a, ,,,, I No RA IUPAC
name 0 I
t.) o .., 3-amino-N-[(10R,13S)-10-methy1-12,18,18-trioxo-8-oxa-18A6-thia-11,21-c,.) w INH2 diazatricyclo[17.3.1.02,1tricosa-1(23),2,4,6,19,21-hexaen-13-yl]propanamide 0, o ili N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18A6-thia-11,21-diazatricyclo[l 7.3.1.021tricosa Ex.180 - --.1 -11, '00 1(23),2,4,6,19,21-hexaen-13-y1]-2-(1-naphthyl)acetamide Ex.181 _ 0 410/10 N-[(10R,13 S)-10-methyl-12,18,18-trioxo-8-oxa-18A6-thia-11,21-d iazatricyclo[17.3.1.021tricosa--N
H 1(23),2,4,6,19,21-hexaen-13-y1]-2-(2-naphthyl)acetamide I
Ex. -'1\1)L,...,CF3 3,3,3-trifluoro-N-[(10R,13S)-10-methy1-12,18,18-trioxo-8-oxa-18A6-thia-11,21- P
i .

N, diazatricyclo[17.3.1 .021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]propanamide _., o .
3-fluoro-N-[(1-10-methy1-12,18,18-trioxo-8-oxa-18A6-thia-11,21-"
Ex.183 . F
'NH 0 . .
I, .
, diazatncyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-ylibenzamide 0-) , , 0,,IV ---'7' N-[(10R,13S)-10-methy1-12,18,18-trioxo-8-oxa-18A6-thia-11,21-diazatricyclo[17.3.1.021tricosa N-.
Ex.184 - ,u... -.. N
-"--H H 1(23),2,4,6,19,21-hexaen-13-y1]-1V-(3-pyridinyOurea Ex.185 N-methyl-Af-[(10R,13 S)-10-methy1-12,18,18-trioxo-8-oxa-18A6-thia-11,21-1.1 ill diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]urea tert-butyl 3-[({[(10R,13S)-10-methy1-12,18,18-trioxo-8-oxa-18A6-thia-11,21-1-t I
Ex.186 --NH^,11-0-1< diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13- n ,-tt yliaminolcarbonyl)amino]propanoate ot k..) o , 3-[({[(10 R,13S)-10-methy1-12,18,18-trioxo-8-oxa-18A6-thia-11,21-,¨

t..) , o I
Ex.187 MNN---iLOH
H H diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13- c.., CA
C.) CT
co yllamino}carbonyl)amino]propanoic acid I
i , No RA IUPAC
name 0 ,-, (302 N-[(I0R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18A6-thia-11,21-diazatricyclo[17.3.1 .021tricosa- c,4 Ex.188 c..4 H 1(23),2,4,6,19,21-hexaen-13-ylynethanesulfonamide vz, c, 0 , N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18A6-thia-11,21-diazatricyclo[17.3.1.02,7]tricosa-Ex.189- ,S' -I1 1(23),2,4,6,19,21-hexaen-13-yl]cyclopropanesulfonamide 0, ,0 Ex.190 ''NS' 0 N-[(10R,13 S)-10-methyl-12,18,18-trioxo-8-oxa-18A6-thia-11,21-d iazatricycl or 7.3.1.021tricosa- , H 1(23),2,4,6,19,21-hexaen-13-ylibenzenesulfonamide ' Ex.191 methyl N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18A6-thia-11,21- P
N, A diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-ylicarbamate .3 _., 2-ethoxyethyl N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18A6-thia-11,21-.
Ex.192 - 1 m N).
1 diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate r...) , cs) , .
Table 22a: Examples of Core 10 (Ex.193a, c-h and Ex.194b; continued on the following page) General Purification No Fmoc-AA1-0H Fmoc-AA2-0H
Yield (isolated salt) 1 Procedure Method prep. HPLC
ht Ex.193a C.1 Fmoc-63-homoPhe-OH Fnnoc-NMe-DAla-OH 20 mg / 53% n method 2b ' prep. HPLC *d w Ex.193c C.1 Fmoc-13-Ala-0H Fmoc-NMePhe-OH
7 nng / 19% <>
)--, method 2b f.,J
-..., (=
u, prep. HPLC
Ex.193d C.1 Fmoc-6-Ala-OH Fmoc-Phe-OH
2 mg /6% (..) method 2b ot , General Purification 0 , No Fmoc-M1-0H Fmoc-AA2-0H
Yield (isolated salt) r..) i Procedure Method w prep. HPLC
HPLC t..) Ex.193e 0.1 Fmoc-NMe-133-homoDAla-OH
Fnnoc-NMePhe-OH 7 mg /18%
method 2b -.1 prep. HPLC
Ex.193f 0.1 Fmoc-NMe-63-homoDAla-OH Fmoc-Sar-OH
9 mg / 27%
method 2b prep. HPLC
Ex.193g 0.1 Fmoc-NMe-63-homoDAla-OH Fmoc-Phe-OH
8 mg / 22%
method 2b prep. HPLC
Ex.193h 0.1 Fmoc-63-homoPhe-OH Fnnoc-NMe-f3-Ala-OH 13 mg /33% P
method 2b .
r., prep. HPLC -, Ex.194b 0.1 Fmoc-NMe-63-homoDAla-OH Fmoc-NMe-Glu(OtBu)-OH 14 mg /31%
method la N.) , cy) .
, ch .
i/
Table 22b: Examples of Core 10 (Ex. 193a, c-h and Ex. 194b; continued on the following page) Monoisotopic Rt (purity at No Formula [M+H]- found LC-MS-Method Mass 220nm) Ex.193a C31H34N404 526.2 2.03 (99) 527.2 method 1d )-cf Ex.193c C30H32N404 512.2 1.94 (94) 513.0 method 1d n Ex.193d C29H30N404 498.2 1.80 (93) 499.2 method 1d ot ta Ex.193e C32H36N404 540.2 2.07 (86) 541.2 method 1d .., w Ex.193f C25H30N404 450.2 1.50 (99) 451.2 method 1d CS
cm c..) Ex.193g C31H34N404 526.2 1.94 (98) 527.2 method 1d ez, oo Ex.193h 031H34N404 526.2 1.78 (98) 527.2 method 1d Monoisotopic Rt (purity at No Formula [M+H]4 found LC-MS-Method Mass 220nm) Ex.194b C28H34N406 522.2 1.68 (97) 523.2 method 1d Table 22c: Examples of Core 10 (Ex. 193a, c-h and Ex. 194b) (continued on the following page) No IUPAC name (9 S,16S,19 R)-16-benzy1-19,20-d imethy1-7-oxa-13,17,20,24-Ex.193a tetraazatetracyclo[20.3.1.12,6.09,13]heptacosa-1(26),2(27),3,5,22,24-hexaene-14,18,21-trione (9S,19S)-19-benzy1-20-methy1-7-oxa-13,17,20,24-tetraazatetracyclo[20.3.1.12,6.09,13]heptacosa-Ex.193c 1(26),2(27),3,5,22,24-hexaene-14,18,21-trione cs) (9S,19S)-19-benzy1-7-oxa-13,17,20,24-tetraazatetracyclo[20.3.1.12,6.09,13]heptacosa-Ex.193d 1(26),2(27),3,5,22,24-hexaene-14,18,21-trione (9S,16R,19S)-19-benzy1-16,17,20-trimethy1-7-oxa-13,17,20,24-Ex.193e tetraazatetracyclo[20.3.1.12,6.09,13]heptacosa-1(26),2(27),3,5,22,24-hexaene-14,18,21-trione (9S,16R)-16,17,20-trimethy1-7-oxa-13,17,20,24-tetraazatetracyclo[20.3.1.12,6.09,13] heptacosa-Ex.193f 1(26),2(27),3,5,22,24-hexaene-14,18,21-trione (9S,16R,19S)-19-benzy1-16,17-dimethy1-7-oxa-13,17,20,24-Ex.193g tetraazatetracyclo[20.3.1.12,6.09,13]heptacosa-1(26),2(27),3,5,22,24-hexaene-14,18,21-trione k=.>
(9S,16S)-16-benzy1-21-methy1-7-oxa-13,17,21,25-tetraazatetracyclo[21.3.1.12,6.09,13]octacosa-Ex.193h 1(27),2(28),3,5,23,25-hexaene-14,18,22-trione oo No IUPAC name r..) 3-[(9S,16R,19S)-16,17,20-trimethy1-14,18,21-trioxo-7-oxa-13,17,20,24-c.4 Ex.194b I¨

f..4 tetraazatetracyclo[20.3.1.12,6.09,13]heptacosa-1(26),2(27),3,5,22,24-hexaen-19-yljpropanoic acid VD
, D =
VD
- - =
Table 23a: Examples of Core 11 (Ex. 195a,b,e-h,j; Ex. 196c,i,k and Ex. 197d;
continued on the following page) , , General Purification Yield (isolated No Fmoc-AA1-0H Fmoc-AA2-0H Fmoc-Procedure Method salt) I
P
Fmoc-NMe-83-prep. HPLC .
Ex.195a 0.2 Fnnoc-Sar-OH
Fmoc-NMeAla-OH 31% "
.3 honnoDAla-OH
method 2a .
-, , Fmoc-NMe-83-prep. HPLC
Ex.195b C.2 Fmoc-Gly-OH Fmoc-Ala-OH 18% o i homoDAla-OH
method 2a , co .
1 Fmoc-NMe-133- Fmoc-NMeGlu(OtBu)- prep. HPLC , , Ex.196c 0.2 Fmoc-Ala-OH
33% (TEA salt) .

homoDAla-OH
OH method la , ' Fmoc-NMe-83-prep. HPLC
Ex.197d 0.2 Fmoc-Lys(Boc)-OH Fmoc-DAla-OH 24%
honnoDAla-OH
method 2a Fmoc-NMe-83-prep. HPLC
Ex.195e 0.2 Fnnoc-Sar-OH
Fmoc-NMeAla-OH 33%
homoDAla-OH
method 2a n Fmoc-NMe-83-prep. HPLC
Ex.195f 0.2 Fmoc-Sar-OH Fmoc-NMeAla-OH
22%
homoDAla-OH
method 2a tl o prep. HPLC
--, (...) Ex.195g 0.2 Fmoc-Gly -OH Frnoc-Phe-OH
Fmoc-NMeDAla-OH 17% --, o method 2a c.,1 C.) C.' prep. HPLC
co Ex.195h 0.2 Fmoc-Sar-OH Fmoc-Phe-OH Fmoc-DAla-OH 13%
method 2a , , I
, ' Fmoc-NMeGlu(OtBu)-prep. HPLC 0 Ex.1961 C.2 Fmoc-Ala-OH Fmoc-DPhe-OH
12% (TEA salt) k=J
OH
method 1a c' 1--, w --.
prep. HPLC
(..) Ex.195j C.2 Fmoc-Sar-OH Fmoc-Phe-OH Fmoc-NMeDAla-OH 13%
o, method 2a _ Fmoc-NMeGlu(OtBu)-prep. HPLC
Ex.196k C.2 Fmoc-DAla-OH Fmoc-Phe-OH
10% (TFA salt) OH
method la Table 23b: Examples of Core 11 (Ex. 195a5b,e-h,j; Ex. 196c,i,k and Ex. 197d) P
r., .3 Monoisotopic Rt (purity at .
No Formula [M+1-1]+ found LC-MS-Method , Mass 220nm) .
Ex.195a C29H37N505 535.3 1.50 (98) 536.2 method 1d rv , o) , c.c.
.
Ex.195b C27H33N505 507.3 1.44 (98) 508.2 method 1d i2-µ
Ex.196c C31H39N507 593.3 1.47 (98) 594.2 method 1d Ex.197d C31H42N605 578.3 2.10 (92) 579.2 method 2f Ex.195e C29H37N505 535.3 1.53 (98) 536.3 method 1d Ex.195f C29H37N505 535.2 1.40 (98) 536.2 method 1d Ex.195g C32H35N505 569.3 1.71 (97) 569.9 method 1d , 1-d Ex.195h C32H35N505 569.3 1.67 (97) 570.2 method 1d n -.3 m Ex.1961 C35H39N507 641.3 1.41 (90) 642.3 method 2f od r.) c>
Ex.195j C33H37N505 583.3 1.72 (93) 584.0 method 1d ..., c..) a Ex.196k C35H39N507 641.3 1.71 (99) 642.2 method 1d c.ik fm f...) c"
co , Table 23c: Examples of Core 11 (Ex.195a,b,e-h,j; Ex. 196c,i,k and Ex. 197d) (continued on the following page) 0 No IUPAC name (9S,16R,22S)-16,17,20,22,23-pentamethy1-7-oxa-13,17,20,23,27-Ex.195a pentaazatetracyclo[23.3.1.12,6.09,13]triaconta-1(29),2(30),3,5,25,27-hexaene-14,18,21,24-tetrone (9S,16R,228)-16,17,22-trimethy1-7-oxa-13,17,20,23,27-pentaazatetracyclo[23.3.1.12,6.09,13]triaconta-Ex.195b 1(29),2(30),3,5,25,27-hexaene-14,18,21,24-tetrone 3-[(9S,16R,19S,22S)-16,17,19,23-tetramethy1-14,18,21,24-tetraoxo-7-oxa-13,17,20,23,27-Ex.196c pentaazatetracyclo[23.3.1.12,6.09,13]triaconta-1(29),2(30),3,5,25,27-hexaen-22-yl]propanoic acid (9S,16R,19S,22R)-19-(4-aminobuty1)-16,17,22-trimethy1-7-oxa-13,17,20,23,27-Ex.197d pentaazatetracyclo[23.3.1.12,6.09,13]triaconta-1(29),2(30),3,5,25,27-hexaene-14,18,21,24-tetrone (9S,19R,22S)-16,19,20,22,23-pentamethy1-7-oxa-13,16,20,23,27-Ex.195e pentaazatetracyclo[23.3.1.12,6.09,13]triaconta-1(29),2(30),3,5,25,27-hexaene-14,17,21,24-tetrone (9S,18S,22R)-16,18,19,22,23-pentamethy1-7-oxa-13,16,19,23,27-Ex.195f pentaazatetracyclo[23.3.1.12,6.09,13]triaconta-1(29),2(30),3,5,25,27-hexaene-14,17,20,24-tetrone (9S,18S,21R)-18-benzy1-21,22-dimethy1-7-oxa-13,16,19,22,26-Ex.195g pentaazatetracyclo[22.3.1.12,6.0903]nonacosa-1(28),2(29),3,5,24,26-hexaene-14,17,20,23-tetrone (9S,18S,21 R)-18-benzy1-16,21-dimethy1-7-oxa-13,16,19,22,26-Ex.195h pentaazatetracyclo[22.3.1.12,6.09,13]nonacosa-1(28),2(29),3,5,24,26-hexaene-14,17,20,23-tetrone 3-[(9S,15S,18R,21S)-18-benzy1-15,22-dimethy1-14,17,20,23-tetraoxo-7-oxa-13,16,19,22,26-Ex.1961 pentaazatetracyclo[22.3.1.12,6.09,13]nonacosa-1(28),2(29),3,5,24,26-hexaen-21-yl]propanoic acid Cli (9S,18S,21 R)-18-benzy1-16,21,22-trimethy1-7-oxa-13,16,19,22,26-Ex.195j pentaazatetracyclo[22.3.1.12,6,09,13]nonacosa-1(28),2(29),3,5,24,26-hexaene-14,17,20,23-tetrone No IUPAC name 0b..) --, 3-[(9S,15R,18S,21S)-18-benzy1-15,22-dimethy1-14,17,20,23-tetraoxo-7-oxa-13,16,19,22,26- w Ex.196k w pentaazatetracyclo[22.3.1.12,6.09,13]nonacosa-1(28),2(29),3,5,24,26-hexaen-21-yl]propanoic acid c7, Table 24a: Examples of Core 12 (Ex.198-Ex.219; continued on the following pages) Starting General No RB RD Reagent Purification Method Yield (isolated salt) Material Proced.
P
Ex.198-Ex.200: cf. experimental description .
r., .3 Formaldehyde -, o .
Ex.201 = .1t. CH3 Ex.200 (A.6.2)1) (36.5% in H20);
FC (CH2C12/Me0H) 89% .
'N e\N"
1., .
H
IV r details cf. 1) --.1 Ø
, Ex.202 NH2 CH3 Ex.201 B.1 HCI-dioxane crude product 93% (HCI salt) 2-Naphthaleneacetic 0 40 acid prep. HPLC
Ex.203 "1 40 CH3 Ex.202 A.1.3 c me 6%
T3P 50% in Et0Athod 2a , , tl i-Pr2NEt (7 equiv.) e) i-i prep. HPLC
tm iv ! 3-Methylbutanoic acid 1,-) o method 1a and prep. o .., Ex.204CH3 Ex.202 A.1.3 T3P 50% in Et0Ac 70/0 (.4 ---HPLC
o H
()) i-Pr2NEt (7 equiv.) (.), (.4 method 2a c, oc i i Starting General No RB RD Reagent Purification Method Yield (isolated salt) Material Proced.
o w prep. HPLC
w CA
3-Pyridinyl isocyanate method 1a and prep. .:, Ex.205 = I QN CH3 Ex.202 A.3 24% -4 -I \I N
=
H H
i-Pr2NEt (5 equiv.) HPLC
method 2a 0,,o Benzenesulfonyl prep. HPLC
= Ex.206 'Id io CH3 Ex.202 A.5 chloride (1.1 equiv.) 68%
i method 2a ' NEt3 (5 equiv.) P

2-(Dimethylamino) Iv 0cm en ' -.J
49% - ...11-, --t, 0 ... acetic acid prep. HPLC
Ex.207 Ex200 A13 ..
'1\I.,1t Ø
H Workup:
CH2Cl2, sat. method 2a lv lv aq. NaHCO3 soln --4 Ø

IV

Ex.208 NH2 ,-LI Ex.207 B.1 HCI-dioxane crude product 85% (HCI salt) prep. HPLC
2-Phenylacetic acid I
9 Ex.209 , 0 40 1 Ex.208 A.1.3 (3.4 equiv.) method 1a and prep.
22%
- 11,,,,,,, N ...,..
HPLC
I H
i-Pr2NEt (8 equiv.) )1t method 2a n )-3 prep. HPLC
)-zi 0N-Succinimidyl N- I.) a) Ex.210 , A __. 9 1 Ex.208 A.3 methylcarbamate method la and prep. ).-, w C`p 'N N õ
38%
1.1--õõ-.N..,, HPLC tr, H H
i-Pr2NEt (5 equiv.) t.n w method 2a c, co Starting General I No Rs RD Reagent Purification Method Yield (isolated salt) r..) , o r Material Proced.
--, , .aHaPnLdCprep. (..) Ex.211 :
'--\/ (1)1,,, Ex.208 A.5 methpordepl ¨1 ..... :s, Cycloperohploarnideesulfonyl , H
30%
HPLC
NEt3 (5 equiv.) method 2a (ii).. Acetyl chloride , Ex.212 --I\1) -. 10 Ex.199 A.1.2.2 FC (CH2C12/Me0H) 68%
(2 equiv.); 0 C, 2 h H
I
P

.3 Ex.213- )(' H Ex.212 B.3 Hz, Pd(OH)2-C, Me0H crude product 86% -, -N
.
H
.
r., tv , 3-Fluorobenzaldehyde -4 1 Ca (1.8 equiv.) prep. HPLC , , Ex.214 '-N)- '' 0 F
Ex.213 A.6.3 Acetic acid (1.5 equiv.) method la and prep.
NaBH(OAc)3 (4 equiv.) HPLC 8%
H
Workup: CHCI3, sat. aq.
method 2a Na2CO3 soln prep. HPLC

it n - ' N jC k., NO Ex.213 A.1.3 1-Pyrrolidineacetic acid method 1a and prep.
Ex.215 14%
HPLC
..i tx1 Fi IL.) o method 2a 1--, f..J
, --.
o cm vi f..) o, oo Starting General No RB RD Reagent Purification Method Yield (isolated salt) ks.) Material Proced.
,-, ' w ,-, =
prep. HPLC w o, A.3 Phenyl isocyanate method la and prep.
, Ex.216 -'NA. --ZN 4110 Ex.213 28%
H H (1.4 equiv.) HPLC
method 2a prep. HPLC

method la and prep.
Ex.217 ' -.N.11,, -S 110/ Ex.213 A.5 Benzenesulfonyl chlorid HPLC 18%
i i H
P
method 2a .
N) .3 .
.

.., , .
Ex.218 ''I\1 -11,-OHTFACH2Cl2 Ex.219 B.2 crude product 87% (TEA salt) .
r., H

, .p.
.
tert.-Butyl 3-((2,5-prep. HPLC , , Ex.219 -- NA-ILN-j< Ex.213 A.3 dioxopyrrolidin-l-yloxy) method la and prep.
49%
H
carbonylamino) HPLC
H
, propanoate method 2a , , 1) At 0 C, formaldehyde (36.5% in H20; 0.48 mL, 6.4 mmol), acetic acid (0.088 mL, 1.5 mmol) and NaBH(OAc)3 (1.09 g, 5.1 mmol) were added to a i soln of Ex.200 (0.635 g, 1.3 mmol) in DOE (20 mL). The mixture was stirred for 2 h at 0 C, followed by an aqueous workup (CH2Cl2, sat. aq.
It n NaNC03 soln; Na2SO4). The crude product was dissolved in MeCN (3 mL) and treated with 25% aq. NH3 soln (1 mL) for 3 h at rt. More 25% aq.
' 1 NH3 soln (1 mL) was added and stirrig was continued for 2 h.
Aqueous workup (Et0Ac, sat. aq. Na2CO3 soln, sat. aq. NaCI soln; Na2SO4) and FC oz r..) (CH2C12/Me0H 9:1) afforded Ex.201 (0.587g, 89%).
w -...
cp ul vi w cr, co ' Table 24b: Examples of Core 12 (Ex.198-Ex.219; continued on the following page) 0 b.) cp ,-.
Monoisotopic Rt (purity at [M+H]- e..4 No RB RD Formula LC-MS-Method ,--c.4 Mass 220nm) found 1/4z C., '.1 Ex.198-Ex.200: cf experimental description o Ex.201A CH3 C27H35N505 509.3 1.58 (97) 510.3 method 2f ''N Cr-\'''=
H
Ex.202 NH2 CH3 C22H27N503 409.2 1.05 (95) 410.0 method 2f 0 a Ex.203 '-ri ii CH3 C34H35N504 577.3 1.58 (97) 578.1 method 2c P
.
o .3 Ex.204 -'N--11-"\. CH3 C27H35N504 493.3 1.38 (99) 494.2 method 2c -, ..
H
Ø
N, ji I

Ex.205 -'I\1- -NQN CH3 C28H31N704 529.2 1.20 (99) 530.2 method 2c n) H H

r , , .
Ex.206 -N-s is CH 3 C28H31N505S
549.2 1.48 (99) 550.1 method 2c H
, , Ex.207 = A --I\,,. (I:I I C30H40N606 580.3 1.18 (98) 581.2 method 1d , 'N
H

I Ex.208 NH2 11 C25H32N604 480.2 1.09 (95) 481.3 method 2f It Ex.209, 0 0 9 1 C33H38N605 598.3 1.44 (98) 599.1 method 2c n i-i '1\I 4...õ,õõN

It Ex.210 C27H35N705 537.3 1.12 (99) 538.2 method 2c .., c...) -.
H H
u, Ex.211 µ'N'µS/ J.L,, C28H36N606S
584.2 1.28 (99) 585.1 method 2c H
, g No RB RD Formula Monoisotopic Rt (purity at [M+H]+ LC-MS-Method r.1 o Mass 220nm) found )--, (.4 .
,..µ

(...) Ex.212 - 'N)(` --11 0 C31H33N506 571.2 1.18 (97) 572.0 method la 47, H .

Ex.213 -'N)L- H C23H27N504 437.2 1.32 (96) 438.1 method 5a H

F
Ex.214 -'N,k, - " 40 C30H32FN504 545.2 1.51 (99) 546.1 method 2c H Q

"
.3 Ex.215 -'1\1) --LO C29H36N605 548.3 1.20 (99) 549.2 method 2c , H
.
r., , 0 N.) .
, 1 Ex.216 -)1,., i 01 'N - N 556.2 1.32 (97) 556.9 method 2c --4 cs) , , H H

0 0õ0 Ex.217 ,, N C29H31N506S 577.2 1.37 (100) 578.1 method 2c H

Ex.218 C27H32N607 552.2 1.50 (92) 553.1 method 5a H
H
it n Ex.219 -'1\1 --ZN-jL0)< C31H40N607 608.3 1.42 (98) 609.2 method 2c H
'V
H
r4 c) --, (...) --..
c, ul ul , c..,J
cA
oe) , Table 24c: Examples of Core 12 (Ex.198-Ex.219; continued on the following pages) 0 b.) cz ,--, No RB RD
IUPAC name (.4 o, 1 benzyl (10S,12S)-12-[(tert-butoxycarbonyl)amino]-15,21-dioxo-8-oxa-3,14,17,20-S
Ex:198 N 0 - 0 H tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaene-17-carboxylate 11,, benzyl (10S,12S)-12-amino-15,21-dioxo-8-oxa-3,14,17,20-Ex. 199 NH2 - - 0 gal WI tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaene-17-carboxylate tert-butyl N-[(10S,12S)-15,21-dioxo-8-oxa-3,14,17,20--.N1 Ex.200 c4.., H
H tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaen-12-yl]carbamate P
tert-butyl N-[(10S,12S)-17-methy1-15,21-dioxo-8-oxa-3,14,17,20-"
Ex.201 ' ,N10,-\\ CH3 H \
tetra azatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaen-12-ylicarbamate .9 .-(2 I
.
(10S,12S)-12-amino-17-methy1-8-oxa-3,14,17,20-'' Ex.202 NH2 CH3 ' tetraazatetracyclo[20.2.2.02,7.010,1hexacosa-1(24),2,4,6,22,25-hexaene-15,21-dione .-.1 -.4 , , , i N-[(105,12S)-17-methy1-15,21-dioxo-8-oxa-3,14,17,20-0 re Ex.203 s-r, 10 CH3 tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4 ,6,22,25-hexaen-12-y1]-2-(1-naphthyl)acetamide , o Ex.204 CH 3 3-methyl-N-[(10S,12S)-17-methy1-15,21-dioxo-8-oxa-3,14,17,20-I --N )c,--",.
I
H tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaen-12-ylibutanamide i cn , N-[(10S,12S)-17-methy1-15,21-dioxo-8-oxa-3,14,17,20-Ex.205 -.NIN-0 CH3 tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaen-12-y1W-(3- ot k=J
H H

i--, pyridinyl)urea (..4 , o (A
(li 4) C"

No RB RD 1UPAC name t.) 0-, N-[(10S,12S)-17-methy1-15,21-dioxo-8-oxa-3,14,17,20-(..) 0õ ,p .
L.) Ex.206 ''N's 0 CH3 tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaen-12-o, H
---.1 yl]benzenesulfonamide o 0 1 tert-butyl N-[(10S,12S)-17-[2-(dimethylamino)acety1]-15,21-dioxo-8-oxa-3,14,17,20-Ex.207 = ,N)1,0-1--, , N
H \ - ' L "-- tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaen-12-yl]carbamate 0 1 (10S,12S)-12-amino-17-[2-(dimethylamino)acety1]-8-oxa-3,14,17,20-Ex.208 NH2__ II , -.....õ,õN=--. tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaene-15,21-dione P
N-[(I0S,12S)-17-[2-(dimethylamino)acety1]-15,21-dioxo-8-oxa-3,14,17,20-rõ
.3 0 gal Ex.209 __11_t traazat tracycI [20.2.2.02,7 .01 ,14 hexacosa-1 (24) 2 4 6 22,25 hexaen-12- 1]-2 -phenylacetamide .,..o.
"
=, r.) , 0 N-[(10S,12S)-17-[2-(dimethylamino)acety1]-15,21-dioxo-8-oxa-3,14,17,20- co , , Ex.210 - A -- II 11\1 tetraazatetracyclo[20.2.2.02.7.010,14Thexacosa-1(24),2,4,6,22,25-hexaen-12-y1FM-'11 H ---"--- .
methyl u rea 0 ,'O N-[(10S,12S)-1742-(dimethylamino)acety1]-15,21-dioxo-8-oxa-3,14,17,20-- µs.,.... .
Ex.211 -N v il /1,1 tetraazatetracyclo[20.2.2.02,7.010,141 ihexacosa-1(24),2,4,6,22,25-hexaen-12-------- N.
yl]cyclopropanesulfonamide It 0r) Ex.212 ' -1\1 '-'1C SI benzyl (10 S,12S)-12-(acetylamino)-15,21-dioxo-8-oxa-3,14,17,20-m tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaene-17-carboxylate ,To H
r.) 0., Ex.213 ''N'k H N-[(10S,125)-15,21-dioxo-8-oxa-3,14,17,20-tetraazatetracyclo[20.2.2.02,7.010141hexacosa (.4 , o ur, 1(24),2,4,6,22,25-hexaen-12-yl]acetamide u, (.4 H
c, oo No RB RD , IUPAC name o Ex.214 --N-k- ,.. 0 F N-[(10S,12S)-17-(3-fluorobenzy1)-15,21-dioxo-8-oxa-3,14,17,20- f..4 ,-.
c..J
H

tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaen-12-yl]acetamide o, i 0 N-[(10S,12S)-15,21-dioxo-1742-(1-pyrrolidinyl)acety1]-8-oxa-3,14,17,20-Ex.215 --1\1 õLO
tetraazatetracyclo[20.2.2.02,7.010,11hexacosa-1(24),2,4,6,22,25-hexaen-12-yl]acetamide H

Ex.216 '- --1-1--. 1 40 (10S,12S)-12-(acetylamino)-15,21-dioxo-N-pheny1-8-oxa-3,14,17,20-N - N
tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaene-17-carboxamide , H H
..... ..Aõ.. , is P
Ex 217 N-[(l-15,21-dioxo-17-(phenylsulfony1)-8-oxa-3,14,17,20-"
N .3 tetraazatetracyclo[20.2.2.02,7.010,14Thexacosa-1(24),2,4,6,22,25-hexaen-12-yl]acetamide H
, 0 3-({[(10S,12S)-12-(acetylamino)-15,21-dioxo-8-oxa-3,14,17,20- "
Ex.218 ''N)-co - IN -jLofi tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaen-17-H
u, H
' , yl]carbonyl}amino)propanoic acid .
0 tert-butyl 3-({[(10S,12S)-12-(acetylamino)-15,21-dioxo-8-oxa-3,14,17,20-Ex.219 -`N). --IZN-j-Lo tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaen-17-H
H yl]carbonyllamino)propanoate n m ,t l,4 I-, (,) CA
CA
4) CA

, Table 25a: Examples of Core 13 (Ex.220-Ex.226; continued on the following pages) 0 b..1 Starting General e.
No RB RE
Reagent Purification Method Yield (isolated salt) w , ,-, Material Proced.
w \o o, \o Ex.220-Ex.222 of experimental description --.1 2-Phenylacetic acid i-Pr2NEt added at 0 C
Ex.223 , 0 Op CO2CH3 Ex.222 A. 0 C to rt, 2 h FC (CH2C12/Me0H) 93%
N' H Workup: Et0Ac, 1M aq.
HCI soln, H20, sat. aq.
P
NaHCO3 soln r., ...

.
FC (CH2C12/Me0H) -, ..

N
Ex.224 , 0 CO2H Ex.223 B.5 Trimethyltin hydroxide and prep. HPLC
80% ' ..
r., ' H
Ø
method la co , o .
, Ammoniun chloride (5.2 , equiv.) , HATU (3.2 equiv.) ! HOAt (3.2 equiv.) Ex.225 s /10 CONH2 Ex.224 A.2 i-Pr2NEt (8.4 equiv.) FC
(CH2C12/Me0H) 64%
..1\1 H
Workup: Et0Ac, 1M aq.
n HCI soln, H20, sat. aq.

' NaHCO3 soln, sat. aq.
t!
r.e o NaCI soln --, c..) O' ut ch c...>
c"
cc Starting General No RB RE Reagent Purification Method Yield (isolated salt) t.I
Material , Proced.
1¨

µ..) ,-, lsobutylamine c.4 Workup: Et0Ac, H

, Ex.226 õ 0 .- ir N ,,,..õ--..
Ex.224 A.2 1M aq. HCI soln, H20, FC (CH2C12/Me0H) 80%
N
H o sat. aq. NaHCO3 soln, , sat. aq. NaCI soln .
P
Table 25b: Examples of Core 13 (Ex.220-Ex.226) .
"
.3 _.]
No RB RE Formula Monoisotopic Rt (purity at [M+1-1]+ LC-MS-Method ..' "
.
Mass 220nm) found iv , oo , .
, Ex.220-Ex.222.: cf experimental description , , Ex.223 , 40 623.2 2.31 (99) 624.3 method 1d , 'NI
H
Ex.224 CO2H C31H32FN307S 609.2 2.05 (99) 610.2 method 1d 'N
H
1 0.
Ex.225 CONH2 C31H33FN406S 608.2 1.93 (99) 609.2 method Id I 'N
H
n Ex.226 , --rN C35H41FN406S 664.3 2.22 (89) 665.3 method 1d t..) ,.., tm c., c, 0, , Table 25c: Examples of Core 13 (Ex.220-Ex.226) k..) cz ,--, No RB RE i UPAC name w ,...
w methyl (8 S,17S,19S)-1 7-[(tert-butoxycarbonyl)amino]-24-fluoro-6,14-dioxo-10,21-dioxa-4-o, Ex.220 -.N10--\,, CO2CH3 thia-7,15-diazatetracyclo[20.3.1.125.015,19]heptacosa-1(26),2,5(27),12,22,24-hexaene-8-carboxylate methyl (8 S,17S,19S)-17-[(tert-butoxycarbonyl)am ino]-24-fluoro-6,14-dioxo-10,21-dioxa-4-Ex.221 = , CO2CH3 thia-7,15-diazatetracyclo[20.3.1.12,5.015,19]heptacosa-1(26),2,5(27),22,24-pentaene-8-' _ carboxylate P
methyl (8S,17S,19S)-17-amino-24-fluoro-6,14-dioxo-10,21-dioxa-4-thia-7,15-rõ
Ex.222 NH2 CO2CH3 ..]
diazatetracyclo[20.3.1.12,5.015,11heptacosa-1(26),2,5(27),22,24-pentaene-8-carboxylate .
methyl (8S,17S,19S)-24-fluoro-6,14-dioxo-17-[(2-phenylacetyl)amino]-10,21-dioxa-4-thia-, op , Ex.223 ='N 0 CO2CH3 7,15-diazatetracyclo[20.3.1.125.015,19]heptacosa-1(26),2,5(27),22,24-pentaene-8-rv .
, H
H
carboxylate (8S,17S,19S)-24-fluoro-6,14-dioxo-17-[(2-phenylacetyl)amino]-10,21-dioxa-4-thia-7,15-Ex.224 -'IN 40 CO2H
H diazatetracyclo[20.3.1.12,5.015,11heptacosa-1(26),2,5(27),22,24-pentaene-8-carboxylic acid (8S,17S,19S)-24-fluoro-6,14-dioxo-17-[(2-phenylacetyl)amino]-10,21-dioxa-4-thia-7,15-Ex.225 -.1\1 0111 CON H2 , H diazatetracyclo[20.3.1.12,5.015,19Theptacosa-1(26),2,5(27),22,24-pentaene-8-carboxamide i 0-3 (8S,17S,19S)-24-fluoro-N-isobuty1-6,14-dioxo-17-[(2-phenylacetyl)amino]-10,21-dioxa-4- n , H
Ex.226 ='1\1 o OP ' Tr N
''' thia-7,15-diazatetracyclo[20.3.1.12,5.015,19]heptacosa-1(26),2,5(27),22,24-pentaene-8-t 1.4 )--, carboxamide w -,--.
,A
.r., .0 Table 26a: Examples of Core 14 (Ex.227-Ex.241; continued on the following page) 0 t=J
i =
Starting General 1¨

No RB RE Reagent Purification Method Yield (isolated salt) c..4 S.-Material Proced.
w C.' , Ex.227-Ex.229: cf. experimental description 2-Naphthaleneacetyl Ex.230 0 040 CO2CH3 Ex.229 A.1.2 chloride prep. HPLC method 3 57%
H
(1.1 equiv.) o I
FC
Ex.231- = A 1 Ex.228 A.2 Isobutylannine 40%
'N
(hexane/Et0Ac/Me0H) P
.
N) Ex.232 NH2 ,TIL.
- FN(Y Ex.231 B.1 HCI-dioxane crude product 93% (HCI salt) .3 -, ..
..
N) .
Nicotinic acid rv , ..
oc) , o.) .
, (1.3 equiv.), ' , , o 0 C, 2 h Ex.233 ''N N - - Z N -'",,,' Ex.232 A.1.1 Workup : FC (CH2C12/Me0H) 14%
1 H L...j.., H 1 Et0Ac, 1M aq. HCI
, soln, sat. aq. Na2CO3 i soln, sat. aq. NaCI soln o ,9d n Ex.2340 1- Ex.228 A.2 Aniline FC (hexane/Et0Ac) 4% i H
M
, *CI
1,4 o Ex.235NH2 Ex.234 B.1 HCI-dioxane prep. HPLC method 1a 44% (TFA salt) ...µ
f.A
--okri 0 --.
e CA
, CA

Phenylacetyl chloride Ex.236 , 40 CO2CH3 Ex.229 A.1.2 prep. HPLC method 3 75% f..4 C.' cot 'NI
H (1.1 equiv.) Starting General No RB RE Reagent Purification Method Yield (isolated salt) Material Proced.
cp I-, w , 0 40 ,--w Ex.237 _ CO2H Ex.236 B.5 Trimethylthin hydroxide prep. HPLC method 1a 78%
' N
0\
' H

--/
3-Chlorobenzoyl Ex.238 --H 40 a CO2CH3 Ex.229 A.1.2 chloride prep. HPLC method 3 62%
, (1.1 equiv.) , 0 Ex.239a coH Ex.238 B.5 Trimethyltin hydroxide prep. HPLC method la 70%

, , FC
P
Ex.240 SO ,YLN.--,,, Ex.241 A.2 lsobutylamine 78% .

(hexane/Et0Ac/Me0H) "

.
-, ..
Ex.241 SO CO2H Ex.230 B.5 Trimethyltin hydroxide FC (CH2C12/Me0H) 84% .
..
H
Iv o N.) F-µ
OD
al.
i 41.
.
H' Table I Table 26b: Examples of Core 14 (Ex.227-Ex.241; continued on the following page) Monoisotopic Rt (purity at No RB RE Formula [M+1-1]+ found LC-MS-Method Mass 220nm) Ex.227-Ex.229: cf. experimental description *d Ex.230 o 00 CO2CH3 C37H36FN3078 685.2 2.28 (96) 686.2 method la n )-3 H
rkl 0't Ex.231 ''IVA0 "-CI) C33H43FN4078 658.3 2.37 (95) 659.3 method 1a o 1--, cA
H
---.

tit ci) w Ex.232 NH2 ,IN.^-," C28H35FN4058 H I 558.2 1.59 (93) 559.2 method 1a 0, oo , , Monoisotopic Rt (purity at i No RB RE Formula [M+HP- found LC-MS-Method t.) =
F., Mass 220nm) c.4 c,4 , , Ex.233 ''N-LN --(131-1\r- C34H38FN506S 663.3 1.95 (87) 664.3 method 2c c, H 1.........).

_ Ex.234 -.N-11-.01.._ -,TLN 0 C35H39FN407S 678.3 2.43 (77) 679.2 method 1a , H H
Ex.235 ,, NH 2 õIL.N

C30H31FN405S 578.2 1.66 (95) 579.2 method 1a i P
1, Ex.236 -'N 40 CO2CH3 C33H34FN307S 635.2 2.15 (91) 636.0 method 1a .
r., ,J
Ø
Ex.237 -µ1\1 40 CO2H C32H32FN307S 621.2 1.98 (96) 622.1 method 1c H Iv N r Ø

Ex.238 '111 0 a CO2CH3 C32H31CIFN307S 655.2 2.31 (97) 656.1 method la ' Ex.239 --N 0 a CO2H C31H29CIFN307S 641.1 2.14 (97) 642.1 method 1a H
Ex.240 - µ1,1 0 400 .-c-i-H H C40H43FN406S 726.3 2.32 (79) 727.3 method 1a Ex.241 -,0 OW CO2H C36H34FN307S 671.2 2.15 (88) 672.1 method 1a ' H
)t n , tml , .1:1 ts.) o ..., (.4 -.._ o (..,, (A
(.4 i ,z co , , , Table 26c: Examples of Core 14 (Ex227-Ex.241; continued on the following pages) 0 t.) =
,-, No RB RE
IUPAC name w , (.4 methyl (8S,12E,18S,20S)-18-[(tert-butoxycarbonyl)amino]-25-fluoro-6,15-dioxo-10,22-o, o -.., Ex.227= A CO2CH3 dioxa-4-thia-7,16-diazatetracyclo[21.3.1.125.016,20]octacosa-1(27),2,5(28),12,23,25--N 0--\---h exa en e-8-ca rboxylate o - A (8S,12E,18S,20S)-18-[(tert-butoxycarbonyl)amino]-25-fluoro-6,15-dioxo-10,22-dioxa-4-Ex.228 'N ol`==
CO2H thia-7,16-d iazatetracyclo[21.3.1.125.016,20]octacosa-1(27),2,5(28),12 ,23,25-hexaene-8-carboxylic acid , P
, methyl (8S,12E, 18S,20S)-18-amino-25-fluoro-6,15-dioxo-10,22-dioxa-4-thia-7,16- o "
i Ex.229 NH2 CO2CH3 a.
, diazatetracyclo[21.3.1.125.016,20]octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxylate , methyl (8 S,12E, 18S,20S)-25-fluoro-18-[2-(2-naphthyl)acetyl]amino-6,15-dioxo-10,22- "
, Ex.230 , 1 tePw- CO2CH3 dioxa-4-thia-7,16-diazatetracyclo[21.3.1.125.018,20]octacosa-1(27),2,5(28),12,23,25- cs) o H

, r hexaene-8-carboxylate .
i tert-butyl N-[(8S,12E, 18S,20S)-25-fluoro-8-Risobutylamino)carbonyI]-6,15-dioxo-10,22-Ex.231 ',NI --",.. 1 dioxa-4-thia-7,16-diazatetracyclo[21.3.1.12,5.016,20]octacosa-1(27),2,5(28),12,23,25-hexaen-H - NY
' 18-yl]carbam ate Ex.232 NH2 ,II Nõ--õ,,, (8S,12E,18S,20S)-18-amino-25-fluoro-N-isobuty1-6,15-dioxo-10,22-dioxa-4-thia-7,16-Iv - hi I diazatetracyclo[21.3.1.1 2,5.
016,21octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxamid e n i--3 (8S,12E,18S,20S)-25-fluoro-N-isobuty1-6,15-dioxo-18-[(3-pyridinylcarbonyl)amino]-10,22- t 1,4 =
Ex.233 - -NI --I N ,.-3,-N---'' dioxa-4-thia-7,16-diazatetracyclo[21.3.1 .125.016,20]octacosa-1(27),2,5(28),12,23,25- i.., H &.,.....j H I Ø
u, hexaene-8-carboxamide u, (..., o No RB RE IUPAC name tert-butyl N-[(8S,12E,18S,20S)-8-(anilinocarbony1)-25-fluoro-6,15-dioxo-10,22-dioxa-4-thia- c.4 Ex.234 A SI 7,16-di azatetracyclo[21.3.1.125.016,20]octacosa-1(27),2,5(28),12 ,23,25-hexaen-18-H H
yl]carbamate o (8S,12E,18S,20S)-18-amino-25-fluoro-6,15-dioxo-N-pheny1-10,22-dioxa-4-thia-7,16-Ex.235 NH2 diazatetracyclo[21.3.1.12,5.016,20]octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxamide methyl (8S,12E,18S,20S)-25-fluoro-6,15-dioxo-18-[(2-phenylacetyl)amino]-10,22-dioxa-4-Ex.236 CO2CH3 thia-7,16-diazatetracyclo[21.3.1.125.016.20]octacosa-1(27),2,5(28),12,23,25-hexaene-8-H
carboxylate (8S,12E,18S,20S)-25-fluoro-6,15-dioxo-18-[(2-phenylacetyl)amino]-10,22-dioxa-4-thia-Ex.237 4111 CO2H 7,16-diazatetracyclo[21.3.1.12,5.016,20]octacosa-1(27),2,5(28),12,23,25-hexaene-8-CO
carboxylic acid methyl (8S,12E,18S,20S)-18-[(3-chlorobenzoyl)amino]-25-fluoro-6,15-dioxo-10,22-dioxa-4-Ex.238 410 cl CO2CH3 thia-7,16-diazatetracyclo[21.3.1.125.016,21octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxylate (8S,12E,18S,20S)-18-[(3-chlorobenzoyl)amino]-25-fluoro-6,15-dioxo-10,22-dioxa-4-thia-Ex.239 a CO2H 7,16-diazatetracyclo[21.3.1.125.016,20]octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxylic acid (8S,12E,18S,20S)-25-fluoro-N-isobuty1-18-{[2-(2-naphthyDacetyliamino}-6,15-dioxo-10,22- k=J
Ex.240 ISO dioxa-4-thia-7,16-diazatetracyclo[21.3.1.12,5.016,20]octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxamide , No RB RE
IUPAC name 0 t.) o --, (8S,12E,18S,20S)-25-fluoro-18-([2-(2-naphthyl)acetyl]amino}-6,15-dioxo-10,22-dioxa-4- c..) ,¨

Ex.241 . 00 CO2H thia-7,16-diazatetracyclo[21.3.1.12,5.016,201 joctacosa-1(27),2,5(28),12,23,25-hexaene-8-t.4 ez, H
--.1 carboxylic acid Table 27a: Examples of Core 15 (Ex.242-Ex.261; continued on the following pages) P
Starting General .
No RB RE Reagent Purification Method Yield (isolated salt) r., , Material Proced.
..
, ..
Ex.242-Ex.244: cf experimental description r., .
M
, ..
Ex.245 CO2CH3 Ex.244 1) 2-Naphthaleneacetyl FC (Et0Ac) and FC
52%
a) , l0 .11 chloride (CH2C12/Me0H) , , Ex.246- N
o Ex.243 2) Aniline (5 equiv.) FC (hexane/Et0Ac) 62%
ENI
- 0 , -H
Ex.247 NH2 -..ICt N Ex.246 2) HCI-dioxane FC (CH2C12/Me0H) 60% (HCI salt) then TEA, CH2Cl2 H
n Phenylacetyl chloride FC
Ex.248 , 010 CO2CH3 Ex.244 A.1.2 90%
,..d -1\I
H (1.6 equiv.) (hexane/Et0Ac/Me0H) --tl-'IV
Ex.249 _ '11 0 CI CO2H Ex.250 B.5 Trimethyltin hydroxide prep. HPLC method 1a 65% t.) o )--, c..4 --...
o 3-Chlorobenzoyl CA

(A
CA
Ex.250 .
-r, 40 CI CO2CH3 Ex.244 A.1.2 chloride FC (hexane/Et0Ac) 87% c, co (1.6 equiv.) ..

Starting General p No RB RE
Reagent Purification Method Yield (isolated salt) It.) Material Proced.
)...
c..) .., Ex.251 0CO2H Ex.248 B.5 Trimethyltin hydroxide prep. HPLC method 1a 700/0 w vD
N
CA
H
Ex.252 0 00 CO2H Ex.245 B.5 Trimethyltin hydroxide prep. HPLC
method 1a 45% --I
H
Isobutylamine (1.5 equiv.) o o Workup:
Ex.253IL Ex FC (hexane, Et0Ac) 73%
N)Lo"-V- -- Eli . 243 A.2 CH2C12, sat. aq.
P
NaHCO3soln, H20, .
N) .3 sat.aq. NaCI soln .
.., o .
Ex.254 NH2 ,-ILN----.---- Ex.253 B.1 HCI-dioxane crude product quant. (HCI salt) r., .
, H
Co Ø

c0 Nicotinic acid , , (1.3 equiv.) o o 0 C, 2 h Ex.255 Ex.254 A.1.1 FC (CH2C12/Me0H) 50%

.....õ----- H Workup: Et0Ac, sat.
aq. NaHCO3soln, H20, sat. aq. NaCI soln, ht Ex.256 = Z Ex.243 2) 4-Chloroaniline FC (hexane/Et0Ac) 14% H
, -11 cy-\-- -- N "Pi (5 equiv.) 1 lt.e CI
HCI-dioxane cp --, 1 Ex.257 NH2 - N "III Ex.256 2) FC (CH2C12/Me0H) 66% (HCI salt) w ---.
ait then TFA, CH2Cl2 c:
(..1 H
ti) 0 Ex.243 2) m-Toluidine w o, cc Ex.258 FC (hexane/Et0Ac) 43%
-'1\1)1'-'0"\''' -IN
H H (5 equiv.) , , Starting General No RI3 RE Reagent Purification Method Yield (isolated salt) t=J
Material Proced.

(6, ,z HCI-dioxane 1-a Ex.259 NH2 Ex.258 2) FC (CH2C12/Me0H) 66% (HCI salt) .0 - N "IP. then TEA, CH2Cl2 H

Ex.260 -,N)1-.0 , IL Benzylamine FC (hexane/Et0Ac) 57%
H - H Ex.243 3) 0 (5 equiv.) o Ex.261 NH2 õ LL. N 0 Ex.260 3) HCI-dioxane FC (CH2C12/Me0H) 74% (HC1salt) H then TEA, CH2Cl2 1) 2-Naphthaleneacetic acid (41 mg, 0.22 mmol) in CH2Cl2 (3 mL) was treated at 0 C for 1 h with oxalyl chloride (0.08 mL, 0.93 mmol) and DMF (0.007 Q
r., mL). The volatiles were evaporated. The residue was dissolved in CH2Cl2 (3 mL) and added dropwise to a mixture of Ex.244-HCI (103 mg, 0.19 .3 -, mmol) and i-Pr2NEt (0.2 mL; 0.93 mmol) in CH2Cl2 (3 mL). The solution was stirred at 0 C for 1 h, followed by an aqueous workup (CH2Cl2, sat. aq. .
r., NaHCO3 soln; Na2SO4), FC (Et0Ac) and FC (CH2C12/Me0H 99:1 to 97:3) to afford Ex.245 (67 mg, 52%). NI .
, cc) .
, 2) Cf. experimental description for detailed procedure o , , 3) Ex.260 was obtained by applying the method described for the saynthesis of Ex.246; Ex.261 was obtained by applying the method described for the ., saynthesis of Ex.247.
, , , , Table 27b: Examples of Core 15 (Ex.242-Ex.261; continued on the following pages) A
Monoisotopic Rt (purity at [M-1-1-1]+ )-No RB RE Formula LC-MS-Method . Mass 220nm) found r.) cz 1-, t.A
Ex.242-Ex.244.: cf experimental description O-vl Ex.245 0 00 CO2CH3 C37H38FN307S 687.2 1.62 (91) 688.2 method 4a (A
t..>
0, H

, , No RB RE Formula Monoisotopic Rt (purity at [M+H]- LC-MS-Method r4 Mass 220nm) found c=
.--.

Ex.246 0 ' sNAOT --j1.'N

C35H41FN407S 680.3 2.48 (86) 681.3 method 1a w C.' H H .
Ex.247 NH2 'IN 41/ C30H33FN405S
580.2 1.66 (96) 581.2 method 1a H
Ex.248 , 0.'N

637.2 2.21 (91) 638.2 method la H

Ex.249 '1E1 0 CI CO2H C31H31CIFN307S 643.2 2.22 (97) 644.1 method 1a Q
N) o .3 Ex.250.
, a CO2CH3 C32H33CIFN307S 657.2 2.40 (94) 658.1 method 1c ..
-,1 0 .
N, .
M
, Ex.251 , 0 0 623.2 2.06 (97) 624.1 method 1a , 'I\1 ._.µ 0 H
.
' r Ex.252 0 so 673.2 2.23 (89) 674.2 method 1g H

Ex.253 C33H45FN407S
660.3 2.45 (93) 661.2 method la -H 0,--\---- H

Ex.254 NH2 AN--N..--- C28H37FN405S
560.2 1.60 (97) 561.2 method la H
, r) Ex.255 '-NI''N -IN---=.,..-' C34H40FN506S
665.3 2.00 (95) 666.2 method 2c 0.3 H H
id o rg ci =-, Ex.256= C35H4OCIFN407S 714.2 2.59 (89) 715.4 method la c..) 'N'll'oT --ILFNI ''..-(A
cn c..1 CI
a, Ex.257 NH2 ?L 0 C30H32CIFN405S
614.2 1.80 (87) 615.2 method 1a 00 H

No RB RE Formula Monoisotopic Rt (purity at [M+1-1]+ LC-MS-Method b.) Mass 220nm) found 1¨

w , .
).., o w Ex.258 'µNAOT --ICLN 4 C36H43FN407S 694.3 2.55 (91) 695.4 method la a, --.) H H
Ex.259 NH2 -I% ill C31H35FN405S 594.2 1.74 (90) 595.3 method 1a - H

,-Ex.260 - \I A0----?LEI C36H43FN407S 694.3 2.44 (92) 695.3 method 1a =IF\
, , P
, .
Ex.261 NH2 ''CLN 0 C31H35FN405S 594.2 1.63 (92) 595.2 method la .3 H
,J
Ø
, .
Ø
Iv IV
r tV

L

Table 27c: Examples of Core 15 (Ex.242-Ex.261; continued on the following pages) No RB RE
IUPAC name methyl (8S,18S,20S)-18-Rtert-butoxycarbonyl)amino]-25-fluoro-6,15-dioxo-10,22-dioxa-o Ex.242 - A. I._ co2cH3 4-thia-7,16-diazatetracyclo[21.3.1.12,5.016,20loctacosa-1(27),2,5(28),23,25-pentaene-8-, 'N 0 H
carboxylate ot n (8S,18S,20S)-18-Rtert-butoxycarbonyl)amino]-25-fluoro-6,15-dioxo-10,22-dioxa-4-thia-o ro Ex.243= ,L.L. CO2H 7,16-di azatetracyclo[21.3.1.12,5.01620]octacosa-1(27),2,5(28),23,25-pentaene-8-carboxylic 14 }-, H
w acid tli COI
t.4 , methyl (8S,18S,20S)-18-amino-25-fluoro-6,15-dioxo-10,22-dioxa-4-thia-7,16- o, Ex.244 NH2 CO2CH3 Go diazatetracyclo[21.3.1.125.016,20]octacosa-1(27),2,5(28),23,25-pentaene-8-carboxylate , , No RB RE IUPAC name methyl (8 S,18S,20S)-25-fluoro-18-([2-(2-naphthyl)acetyl]amino}-6,15-dioxo-10,22-dioxa-Ex.245 140401 CO2CH3 4-thia-7,16-diazatetracyclo[21.3.1.125.016,20]octacosa-1(27),2,5(28),23,25-pentaene-8-carboxylate o tert-butyl N-[(8S,18S,20S)-8-(anilinocarbony1)-25-fluoro-6,15-dioxo-10,22-dioxa-4-thia-Ex.246-Olo 7,16-diazatetracyclo[21.3.1.12,5.016,20]octacosa-1(27),2,5(28),23,25-pentaen-18-hi 0 N
yl]carbamate ,101, (8S,18S,20S)-18-amino-25-fluoro-6,15-dioxo-N-pheny1-10,22-dioxa-4-thia-7,16-Ex.247 NH2 p -diazatetracyclo[21.3.1.12,5.016,20]octacosa-1(27),2,5(28),23,25-pentaene-8-carboxamide co methyl (8 S,18S,20S)-25-fluoro-6,15-di oxo-18-[(2-phenylacetyl)am ino]-10,22-dioxa-4-AM

Ex.248 CO2CH3 thia-7,16-diazatetracyclo[21.3.1.125.016,20]octacosa-1(27),2,5(28),23,25-pentaene-8-carboxylate (A) 0 (8S,18S,20S)-18-[(3-chlorobenzoyl)amino]-25-fluoro-6,15-dioxo-10,22-dioxa-4-thia-7,16-Ex.249 a CO2H
diazatetracyclo[21.3.1.125.01620]octacosa-1(27),2,5(28),23,25-pentaene-8-carboxylic acid methyl (8S,18S,20S)-18-[(3-chlorobenzoyDamino]-25-fluoro-6,15-dioxo-10 ,22-dioxa-4-Ex.250 '11 cl CO2CH3 thia-7,16-diazatetracyclo[21.3.1.12,5.016,20]octacosa-1(27),2,5(28),23,25-pentaene-8-carboxylate (8S,18S,20S)-25-fluoro-6,15-dioxo-18-[(2-phenylacetyl)amino]-10,22-dioxa-4-thia-7,16-Ex.251 o CO2H
diazatetracyclo[21.3.1.125.016,2c]octacosa-1(27),2,5(28),23,25-pentaene-8-carboxylic acid r.a (8S,18S,20S)-25-fluoro-18-{[2-(2-naphthyl)acetyl]amino}-6,15-dioxo-10,22-dioxa-4-thia-u, Ex.252Ti CO2H 7,16-di azatetracyclo[21.3.1.12,5.016 ,20]octacosa-1(27),2,5(28),23,25-pentaene-8-carboxylic acid No RB RE
IUPAC name r.1 o o tert-butyl N-[(8S,-25-fluoro-8-Risobutylamino)carbonyl]-6,15-dioxo-10,22-dioxa-w o ,-w Ex.253 4-thia-7,16-diazatetracyclo[21.3.1.125.016,20]octacosa-1(27),2,5(28),23,25-pentaen-18-H

yl]carbam ate o , (8S,18S,20S)-18-amino-25-fluoro-N-isobuty1-6,15-dioxo-10,22-dioxa-4-thia-7,16-Ex.254 NH2 H
diazatetracyclo[21.3.1.125.016,20]octacosa-1(27),2,5(28),23,25-pentaene-8-carboxamide o o (8S,18S,20S)-25-fluoro-N-isobuty1-6,15-dioxo-18-[(3-pyridinylcarbonyl)amino]-10,22-Ex.255--N-1", N .-11--N------- dioxa-4-thia-7,16-diazatetracyclo[21.3.1.125.016.2c]octacosa-1(27),2,5(28),23,25-H <7, J
H P
, pentaene-8-carboxamide .
rõ
, tert-butyl N-[(8S,-8-[(4-chloroanilino)carbonyl]-25-fluoro-6,15-dioxo-10,22-.3 , o ash a .
Ex.256 - =N )1,01... õ(1)1,,N Ill dioxa-4-thia-7,16-diazatetracyclo[21.3.1.12,5.01620]octacosa-1(27),2,5(28),23,25-pentaen- rõ

m , 18-yl]carbamate .=. .
, , ci (8S,18S,20S)-18-amino-N-(4-chloropheny1)-25-fluoro-6,15-dioxo-10,22-dioxa-4-thia- .
Ex.257 NH2 ,,i)LN 0 7,16-diazatetracyclo[21.3.1.12,5.016,21octacosa-1(27),2,5(28),23,25-pentaene-8-' H
carboxamide , , tert-butyl N-[(8S,18S,20S)-25-fluoro-6,15-dioxo-8-(3-toluidinocarbony1)-10,22-dioxa-4-o Ex.258 = ,N)1,01.... õ Z.,, 0 thia-7,16-diazatetracyclo[21.3.1.125.016,20]octacosa-1(27),2,5(28),23,25-pentaen-18-H
H = d ylicarbamate n (8S,18S,20S)-18-amino-25-fluoro-N-(3-methylpheny1)-6,15-dioxo-10,22-dioxa-4-thia- ot w Ex.259 NH2 -IN 40 7,16-diazatetracyclo[21.3.1.12.5.016,20]octacosa-1(27),2,5(28),23,25-pentaene-8-,--w O.
H
cn carboxamide u, , w o\
oc, ' , No RB RE
IUPAC name 0 k..) =
).-o tert-butyl N-[(8S,-8-[(benzylamino)carbonyI]-25-fluoro-6,15-dioxo-10,22-dioxa-¨.
o ,-, Ex.260 N)1.0 IL
w v:
H H Sp 4-thia-7,16-diazatetracyclo[21.3.1.125.016,20]octacosa-1(27),2,5(28),23,25-pentaen-18-c, yllcarbamate o 11...,, (8S,18S,20S)-18-amino-N-benzy1-25-fluoro-6,15-dioxo-10,22-dioxa-4-thia-7,16-Ex.261 NH2 -- 121 110 diazatetracyclo[21.3.1.125.016,20]octacosa-1(27),2,5(28),23,25-pentaene-8-carboxamide , P
Table 28a: Examples of Core 16 (Ex.262-Ex.283; continued on the following pages) .3 Starting General No RA RF
Reagent Purification Method Yield (isolated salt) .
Material Proced. rõ
co , Ex.262-Ex.264: cf. experimental description I
o 0 so 2-Naphthaleneacetyl Ex.265 H Ex.263 1) FC (CH2C12/i-PrOH) 78%
H i chloride -, 1 Acetic anhydride Ex.266 -.NA, ill Ex.264 A.1.2 prep. HPLC method 1a 58% (TFA salt) , (1.3 equiv.) H
i Ex.267 , . 40 'N 0 H Ex.263 2) 1-Naphthaleneacetyl chloride prep. HPLC method 3 58% )-d n )--i _ tt Isovaleryl chloride o r.) Ex.268 H Ex.263 A.1.2 (1.6 equiv.) prep. HPLC method 3 69%
1--, ''11--k-"---w H
--o 0 C to rt, 16 h to, ui , c,..) o, , , Starting General , No RA RF Reagent Purification Method Yield (isolated salt) w Material Proced.
)-, --.
0¨

o 3-Fluorobenzoyl (.4 o) Ex.269 'Il 0 F H Ex.263 A.1.2 chloride prep. HPLC method 3 52%
--) (1.1 equiv.) 0o Benzenesulfonyl Ex.270 H Ex.263 A.5 prep. HPLC method 3 49%
II
' 0 , chloride 0, ,o , Methanesulfonyl Ex.271 --"SH Ex.263 A.5 prep. HPLC method 3 39%
H chloride P

N) Ex.272- ...-1].. ..- H Ex.263 A.4 Methyl chloroformate prep. HPLC method 3 69% .3 .., 'N 0 ..
H
..

r., o N-Succinimidyl N- iv , Ex.273 -'NAN.- H Ex.263 A.3 prep. HPLC method 3 65%

.
methylcarbamate , , 2,5-Dioxopyrrolidin-1-y1 Ex.274 -N 1N QN H Ex.263 A.3 pyridin-3-ylcarbamate prep. HPLC method 3 64%
' H H
0 C to rt, 1 h o Trimethyloxonium . Ex.275 00 CH3 Ex.265 1) prep. HPLC method la 12%
H
tetrafluoroborate o 11:( Ex.276 ..1,11N 1.161 H Ex.263 1) 2-Naphthylisocyanate prep. HPLC method 3 71% n H H

s Ex.277 H Ex 40 .i:
.263 A.1.1 Phenylacetic acid prep. HPLC method 3 58% r.4 '1\1 --, H
c..4 o -O-m-Anisoyl chloride (A
Ex.278 ..N 40 ..., H Ex.263 A.1.2prep. HPLC method 3 75% (.), (.4 (1.1 equiv.) <7., i Starting General No RA RF Reagent Purification Method Yield (isolated salt) w I Material , Proced.
--, w 2-Naphthalenesulfonyl w Ex.279 '-rs 100 H
Ex.263 A.5prep. HPLC method 3 76%
chloride --.1 3-(4-=
, Ex.280 11 0 H Ex.263 A.1.1 Fluorophenyl)propionic prep. HPLC method 3 42%
F
acid , prep. HPLC method 3 i *
Ex.281 0 NH H Ex.263 A.1.1 1H-indole-3-acetic acid and 38%
'N
P
H
prep. HPLC method 2a .
r., .3 -, ..
Ex.282 -NI O. H Ex.263 A.6.4 Naphthylacetaldehyde prep. HPLC method 2a 26% .
..
r., H

IV
1--µ
(1.3 equiv.) , ---.1 .
Ex.283 'N 101 F H Ex.263 A.6.4 4-Fluorobenzaldehyde prep. HPLC method 3 52% , , 1) Cf. experimental description for detailed procedure 2) Ex.267 was prepared applying the protocol described for the synthesis of Ex.265.
it Table 28b: Examples of Core 16 (Ex.262-Ex.283; continued on the following pages) r) tt No RA RF Formula Monoisotopic Rt (purity at [M+H]+
LC-MS-Method It t,) ,-, Mass 220nm) found w , c.) u, Ex.262 -Ex.264: cf experimental description w Ex.265 . 00 587.2 1.86 (93) 587.9 method la H

, , Monoisotopic Rt (purity at [M+H]+
No RA RF Formula LC-MS-Method 1.1 c) 1--, Mass 220nm) found f,A
.
.., (4 c"
, Ex 266 .
-NA"- C28H33N505S 551.2 1.86 (96) 552.2 method 1d --A
H
0 rim Ex.267 --N mio H C31H33N505S 587.2 1.85 (87) 588.0 method la , ' 1 o ]
Ex.268 '-1\l'iL" H C24H33N505S 503.2 1.54 (98) 504.2 method 1a i H
o Ex.269 'N 0 F H C26H28FN505S 541.2 1.66 (98) 542.1 method 1a P
r., o, ,0 , Ex.270 H C25H29N506S2 559.2 1.58 (97) 560.0 method la ..' -hi 0 N.) , co - _µS/
.
Ex.271 'N '"- H C20H27N506S2 497.1 1.30 (98) 498.0 method 1 a ' , Ex.272 H C21H27N506S 477.2 1.34 (99) 478.1 method la 'N 0 H

1 Ex.273 -'N ).L.N.-- H C21H28N605S 476.2 1.23 (97) 476.9 method la Ex.274 H C25H29N705S 539.2 1.19 (99) 540.0 method 1a H
1-=
*d L.) Ex.2751-, 0 soso CH3 C32H35N505S 601.2 2.05 (97) 602.2 method 1d H
to) CA
Ex.276 ..N1N 00 H C30H32N605S 588.2 1.86 (99) 589.0 method la v, H H

, ,H C27H31N505S 537.2 1.62 (96) 538.2 method la , 0 Ex.277 0 -1\1 H

, "

No RA RF Formula Monoisotopic Rt (purity at [M+H] LC-MS-Method t.4 cp Mass 220nm) found ,--, (.4 ,-, (.4 Ex.2780 ''N 1101 ' H C27H31N506S 553.2 1.65 (96) 554.1 method 1a ,o o, ,0 Ex.279 'Y's' 00 H C29H31N506S2 609.2 1.82 (96) 610.1 method la . 0 Ex.280H C28H32FN505S 569.2 1.72 (92) 570.2 method 1a F
*
Ex.281 0 =-...
NH H C29H32N605S 576.2 1.61 (78) 577.1 method 1a ='N P
H
o Iv a.
Ex.282 --N ONO H C31H35N504S 573.2 1.63 (89) 574.2 method Id .
-, H
al.
Ex.283 11 40 F H C26H30FN504S 527.2 1.37 (97) 528.2 method la , CO

CO
o u, IL
0, Table 28c: Examples of Core 16 (Ex.262-Ex.283; continued on the following pages) , No RA RE
IUPAC name benzyl N-[(9S,11S,15S)-11-[(4-bromobenzyl)oxy]-18,21-dimethy1-14,19-dioxo-7-oxa-3-thia-Ex.262- NYLO
-1-1 ill -- 0 Br 13,18,21,22-tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-*LI
n yl]carbamate m 1.) (9S,11S,15S)-15-amino-11-hydroxy-18,21-dimethy1-7-oxa-3-thia-13,18,21,22-,-, Ex.263 NH2 H
C:D
tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraene-14,19-dione u, Go) (9S,11S,15S)-15-amino-11-(benzyloxy)-18,21-dimethy1-7-oxa-3-thia-13,18,21,22-Ex.264 NH2 - - 00 tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraene-14,19-dione , , No RA RF
IUPAC name 0 t.) cz ,-, N-[(9S,11S,15S)-11-hydroxy-18,21-dimethy1-14,19-dioxo-7-oxa-3-thia-13,18,21,22-w , ,-, Ex.265 = õ, SOS H
tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-y1]-2-(2- w o, H
+:, naphthyl)acetamide II -- is N-[(9S,11S,15S)-11-(benzyloxy)-18,21-dimethy1-14,19-dioxo-7-oxa-3-thia-13,18,21,22-Ex 266 - 'N..- ''''' H
tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-yliacetamide N-[(9S,11S,15S)-11-hydroxy-18,21-dimethy1-14,19-dioxo-7-oxa-3-thia-13,18,21,22-, i 0 /0 1 Ex.267 'IV lit H H
tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-y1]-2-(1- P
naphthyl)acetamide .3 , N-[(9S,11S,15S)-11-hydroxy-18,21-dimethy1-14,19-dioxo-7-oxa-3-thia-13,18,21,22-.
Ex.268 -- H
tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-y1]-3-cA) , H

methylbutanamide o ' i/

3-fluoro-N-[(9S,11S,15S)-11-hydroxy-18,21-dimethy1-14,19-dioxo-7-oxa-3-thia-Ex.269 --[,,, 40 F H 13,18,21,22-tetraazatetracyclo[1 8.2.1.02,6.09.13]tricosa-1(22),2(6),4,20(23)-tetraen-15-yl]benzamide 0 N-[(9 S,11S,15S)-11-hydroxy-18,21-dimethy1-14,19-dioxo-7-oxa-3-thia-13,18,21,22-, ,0 Ex.270 ' h' 101 H
tetraazatetracyclo[18.2.1.02,6.09,11tricosa-1(22),2(6),4,20(23)-tetraen-15-id cn ylThenzenesulfonamide 1-q N-[(9S,1-11-hydroxy-18,21-dimethy1-14,19-dioxo-7-oxa-3-thia-13,18,21,22-ot 0, ,0 - ,µS/
,-Ex.271 'N ' H tetraazatetracycl o[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetrae n-15- w , H u, l y]methanesulfonamide u, w o, co No RA RF IUPAC name Ex.272 L. H
methyl N-[(9S,11S,15S)-11-hydroxy-18,21-dimethy1-14,19-dioxo-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-ylicarba mate N-[(9S,11S,15S)-11-hydroxy-18,21-dimethy1-14,19-dioxo-7-oxa-3-thia-13,18,21,22-H
Ex.273'NAV-H H tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-y1]-1\f-methylurea N-[(9S,11S,15S)-11-hydroxy-18,21-dimethy1-14,19-dioxo-7-oxa-3-thia-13,18,21,22-o Ex.274 ,N N tetraazatetracyclo[1 8.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-y1]-1V-(3-H H
pyridinyl)urea N-[(9S,11S,15S)-11-methoxy-18,21-dimethy1-14,19-dioxo-7-oxa-3-thia-13,18,21,22-Ex.275 0 410 CH3 tetraazatetracycl 8.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-y1]-2-(2-naphthyl)acetamide o.) N-[(9S,11S,15S)-11-hydroxy-18,21-dimethy1-14,19-dioxo-7-oxa-3-thia-13,18,21,22-o Ex.276 H tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-y1]-1V-(2-H H
naphthyl)urea N-[(9S,11S,15S)-11-hydroxy-18,21-dimethy1-14,19-dioxo-7-oxa-3-thia-13,18,21,22-Ex.277 ='N 411H tetraazatetracyclo[18.2.1.0203.09,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-y1]-2-H
phenylacetamide r) N-[(9S,11S,15S)-11-hydroxy-18,21-dimethy1-14,19-dioxo-7-oxa-3-thia-13,18,21,22-. 0 pqi Ex.278 H H tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-y1]-3-methoxybenzamide co , No RA RF
IUPAC name w o --, ; .,,o N-[(9S,1-11-hydroxy-18,21-dimethy1-14,19-dioxo-7-oxa-3-thia-13,18,21,22- w .1,,s Ex.279 00 ,.
. H
tetraazatetracyclo[18.2.1.02,6.09,131tricosa-1(22),2(6),4,20(23)-tetraen-15-y1]-2- cr, naphthalenesulfonamide 3-(4-fluoropheny1)-N-[(9S,11S,15S)-11-hydroxy-18,21-dimethy1-14,19-dioxo-7-oxa-3-thia-Ex.280 .11 di H 13,18,21,22-tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-- F
, yl]propanamide , N-[(9 S,11S,15S)-11-hydroxy-18,21-dirnethy1-14,19-dioxo-7-oxa-3-thia-13,18,21,22-1 .
P
Ex.281 0 NH H
tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-y1]-2-(1H-indoI-3- o Iv -'N
H .., a.
0, ,J
yl)acetamide .
(9S,11S,15S)-11-hydroxy-18,21-dimethy1-15-([2-(2-naphthypethyl]amino}-7-oxa-3-thia- "
c4 , Ex.282 ,r, O. H 13,18,21,22-tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraene-14,19- 2 o , , dione .
(9S,11S,15S)-15-[(4-fluorobenzyl)amino]-11-hydroxy-18,21-dimethy1-7-oxa-3-thia-, . Ex.283 'ENAI 110 H 13,18,21,22-tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraene-14,19-, , F
d Ione , h..$
el 1-i Table 29a: Examples of Core 17 (Ex.284a-Ex.304; continued on the following pages) It k.) (z Starting General ,--.
(.4 No RA RG
Reagent Purification Method Yield (isolated salt) Material Proced.
ui (), t..4 o.
Ex.284a-Ex.286: cf experimental description oc, , Starting General p No RA RG Reagent Purification Method Yield (isolated salt) L=4 Material Proced.
cz .., i w I =
FC (hexane, Et0Ac, 'N
1 Ex.287 0 ''N) Ex.286 1) Acetyl chloride 77% a.
' , Me0H) H

Ex.288 NH2 -'1\1"ks Ex287 B.3 Hz, Pd(OH)2-C, Me0H crude product 78%
H
(1)ci Ex.289 --N-A-N "IP NO2 Ex.285 A.3 1-Chloro-2-FC (hexane, Et0Ac, 90%
H H
isocyanatobenzene Me0H) a alb.
P
Ex.290 = 1 111, NH2 Ex.289 B.4 H2, Pt02 crude product 96% o N) , H H
.
-.J
9CI An Methanesulfonyl 'N'LL
.
' Ex.291 = S
'N WI ' ' N '''. Ex.290 A.5 prep. HPLC
method la 49% (TEA salt) r., H H H chloride (1.2 equiv.) co , C
, Cyclopropanecarboxylic (,.) cn acid, 0 C, 2 h i .
Workup: Et0Ac, FC (hexane, Et0Ac, Ex 292 'N-kv H NO2 Ex.285 A.1.1 70%
1 M aq.HCI soln, Me0H) sat. aq. NaHCO3soln, sat. aq. NaCI soln o it n Ex.293 ''r\rjv NHz Ex.292 B.4 Hz, Pt02 crude product 95% t.
tt H
cz 0 0, ,C) )--Methanesulfonyl w Ex.294''l\lv, Ex.293 A.5 prep. HPLC method la 45% ....
c>
vi H H chloride (1.2 equiv.) u, w e"
oo i ' ;
Starting General ; No RA RG Reagent Purification Method Yield (isolated salt) r.) Material Proced.
1-, (..) Ex.295 NHz Ex.296 13.3 Hz, Pd(OH)2-C, Me0H crude product 86 /() i .1 --C:S µ' `'.
N
H
--.) 0, ,C.
Methanesulfonyl FC (hexane/ Et0Ac) Ex.296 )4 1.I '-N".'S Ex.286 A.5 and prep. HPLC 54%
H chloride (1.2 equiv.) method 3 - 1 N -4--'-'"
Ex.297 .1" O 0 --NNJ Ex.286 2) 2-Chloropyrinnidine FC
(Et0Ac) 38%
P
H
,D
N-7.-`

.., Ex.298 NH2 N __IN j- Ex.297 B.3 H2, Pd(OH)2-C, Me0H crude product 100% ..
..
H
.

co ..
, , /
Formaldehyde .4. .
Ex.299 - -N - - N)1,, Ex.288 A.6.1 prep. HPLC method 1a 50% (TEA salt) , ' \
(36.5% in H20) H
, 2-Phenylacetic acid (2.2 equiv.) , , , HATU (2.5 equiv.) , ' 0 HOAt (2.5 equiv.) Ex.300 , 0 0 - 'N--IL..õ Ex.288 A.1.1 i-Pr2NEt (6 equiv.) prep. HPLC method la 17% (TEA salt) tl 'N
n H H
Workup: Et0Ac, 1M aq.
It HCI sal, sat. aq. r.) 1--, w Na2CO3soln O--v.
v.
(.4 (17, oo DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

NOTE : Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME

NOTE: For additional volumes, please contact the Canadian Patent Office NOM DU FICHIER / FILE NAME:
NOTE POUR LE TOME / VOLUME NOTE:

Claims

1. A compound consisting of a cyclic arrangement of the building blocks A, B
and C and represented by the general formula I
wherein building block A ("Template") is represented by building block B ("Modulator") is represented by building block C ("Bridge") is represented by which in turn consists of and wherein X represents a divalent radical selected from the group of Z represents a divalent or trivalent radical selected from the group of forming an integral part of the Y-Z connectivity which in turn represents a divalent radical selected from the group of U represents a divalent radical selected from the group of V and W are representing independently a divalent radical selected from the group of and wherein said Template A is a bivalent radical consisting of all possible combinations of structure A B¨A c of which A B is selected from the group of and A c is selected from the group of wherein Modulator B is a bivalent radical selected from the group of and Bridge C is a bivalent radical selected from the group of and wherein further R1 and R2 are independently defined as H; F; CI; Br; I; CF3; OCF3; OCHF2;
NO2; CN; C1-24-alkyl; C2-24-alkenyl; C2-10-alkynyl; cycloalkyl;
heterocycloalkyl; aryl;
heteroaryl; aryl-C1-12-alkyl; heteroaryl-C1-12-alkyl; -(CR32R33)q OR34; -(CR32R33)q SR34;
-(CR32R33)q NR7R35; -(CR32R33)q OCONR7R35; -(CR32R33)q NR7COOR36;
-(CR32R33)q NR7COR37; -(CR32R33)q NR7CONR7R35; -(CR32R33)q NR7SO2R38;
-(CR32R33)q NR7SO2NR7R35; -(CR32R33)q COOR36; -(CR32R33)q CONR7R35;
-(CR32R33)q SO2NR7R35; -(CR32R33)q COR37; -(CR32R33)q SO2R38; -(CR32R33)q R39;
-(CR32R33)q R40; -(CR32R33)q R41; or -(CR32R33)q R44;
R3 and R4 are independently defined as H; F; CI; CF3; OCF3; OCHF2; NO2;
CN; C1-24-alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C1-12-alkyl;
heteroaryl-C1-12-alkyl; C1-12-alkoxy or aryloxy;
R5 is H; CF3; C1-24-alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl;
aryl-C1-12-alkyl; or heteroaryl-C1-12-alkyl;
R6 is H; CF3; C1-24-alkyl; C2-24-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl; aryl-C1-12-alkyl; heteroaryl-C1-12-alkyl; -(CR32R33)q OR34; -(CR32R33)q SR34;
-(CR32R33)q NR7R35; -(CR32R33)q OCONR7R35; -(CR32R33)q NR7COOR36;
-(CR32R33)q NR7COR37; -(CR32R33)q NR7CONR7R35; -(CR32R33)q NR7SO2R38;
-(CR32R33)q NR7SO2NR7R35; -(CR32R33)q COOR36; -(CR32R33)q CONR7R35;
-(CR32R33)q SO2NR7R35; -(CR32R33)q COR37; -(CR32R33)q SO2R38; -(CR32R33)q R39;

-(CR32R33)s R40; or -(CR32R33)q R41; or -(CR32R33)q R44;
R7 is H; C1-24-alkyl; C2-24-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1-12-alkyl; heteroaryl-C1-12-alkyl; or an N-protecting group;
R8 and R9 are independently defined as H; F; CF3; C1-24-alkyl; C2-24-alkenyl;
cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C1-12-alkyl; or heteroaryl-C1-12-alkyl;
R10, R11 and R12 are independently defined as H; C1-24-alkyl; or cycloalkyl;
R13 is C1-24-alkyl or cycloalkyl;

R14, R20 and R26 are independently defined as H; F; CF3; C1-24-alkyl; C2-24-alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C1-12-alkyl;
heteroaryl-C1-12-alkyl; -(CR32R33)q OR34; -(CR32R33)q SR34; -(CR32R33)q NR7R35;
-(CR32R33)q OCONR7R35; -(CR32R33)q NR7COOR36; -(CR32R33)q NR7COR37;
-(CR32R33)q NR7CONR7R35; -(CR32R33)q NR7SO2R38; -(CR32R33)q NR7SO2NR7R35;
-(CR32R33)q COOR36; -(CR32R33)q CONR7R35; -(CR32R33)q SO2NR7R35;
-(CR32R33)q COR37; -(CR32R33)q SO2R38; -(CR32R33)q R39; -(CR32R33)s R40;
-(CR32R33)q R41; or -(CR32R33)q R44;
R15, R17, R19, R21 , R23, R25, R27, R29 and R31 are independently defined as H;
C1-24-alkyl; cycloalkyl; or heterocycloalkyl;
R16, R22 and R28 are independently defined as H; CF3; C1-24-alkyl;cycloalkyl;
heterocycloalkyl; aryl; heteroaryl; aryl-C1-12-alkyl; or heteroaryl-C1-12-alkyl;
R18, R24 and R30 are independently defined as H; F; CF3; C1-24-alkyl; C2-24-alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C1-12-alkyl;
heteroaryl-C1-12-alkyl; -(CR32R33)q OR34; -(CR32R33)q NR7R35; -(CR32R33)q OCONR7R35;
-(CR32R33)q NR7COOR36; -(CR32R33)q NR7COR37; -(CR32R33)q NR7CONR7R35;
-(CR32R33)q NR7SO2R38; -(CR32R33)q NR7SO2NR7R35; -(CR32R33)q COOR36;
-(CR32R33)q CONR7R35; -(CR32R33)q SO2NR7R35; -(CR32R33)q COR37; or -(CR32R33)q R44;
R32 is H; F; CF3; C1-24-alkyl; C2-24-alkenyl; cycloalkyl; heterocycloalkyl;
aryl;
heteroaryl; aryl-C1-12-alkyl; heteroaryl-C1-12-alkyl; -(CR51R53)q OR45; -(CR51R53)q SR45;
-(CR51R53)q NR7R45; -(CR51R53)q OCONR7R45; -(CR51R53)q NR74COOR36;
-(CR51R53)q NR7COR37; -(CR51R53)q NR7CONR7R45; -(CR51R53)q NR7SO2R38;
-(CR51R53)q NR7SO2NR7R45; -(CR51R53)q COOR36; -(CR51R53)q CONR7R45;
-(CR51R53)q SO2NR7R45; -(CR51R53)q COR37; -(CR51R53)q SO2R38; -(CR51R53)q R39;
-(CR51R53)s R40; -(CR51R53)q R41; or -(CR51R53)q R44;
R33 is H; C1-24-alkyl, C2-24-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1-12-alkyl; or heteroaryl-C1-12-alkyl;
R34 is H; C1-24-alkyl; C2-24-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1-12-alkyl; heteroaryl-C1-12-alkyl; -(CR51R53)r OR45; -(CR51R53)r NR7R45;

-(CR51R53)r OCONR7R35; -(CR51R53)r NR7COOR36; -(CR51R53)r NR7COR38;
-(CR51R53)r NR7CONR7R45; -(CR51R53)r NR7SO2R38; -(CR51R53)q COOR36;
-(CR51R53)q CONR7R45; -(CR51R53)q SO2NR7R45; -(CR51R53)q COR38;
-(CR51R53)q SO2R38; -(CR51R53)q R39; -(CR51R53)s R40; -(CR51R53)q R41; or -(CR51R53)q R44;
R35 is H; C1-24-alkyl; C2-24-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1-12-alkyl; heteroaryl-C1-12-alkyl; an N-protecting group; -(CR32R33)r OR45;
-(CR32R33)r NR7R45; -(CR32R33)r OCONR7R45; -(CR32R33)r NR7COOR36;
-(CR32R33)r NR7CONR7R50; -(CR32R33)r NR7SO2R35; -(CR32R33)r NR7SO2NR7R50;
-(CR32R33)q COOR36; -(CR32R33)r NR7COR37; -(CR32R33)q CONR7R50;
-(CR32R33)q COR37; -(CR32R33)q SO2R38; -(CR32R33)q SO2NR7R50; -(CR32R33)q R39;

-(CR32R33)s R40; -(CR32R33)q R41; or -(CR32R33)q R44;
R36 is H; C1-24-alkyl; C2-24-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1-12-alkyl; heteroaryl-C1-12-alkyl; or an O/S-protecting group;
R37 is C1-24-alkyl; C2-24-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1-12-alkyl; heteroaryl-C1-12-alkyl; -(CR51R53)q OR45; -(CR51R53)q SR45;
-(CR51R53)q NR7R45; -(CR51R53)q OCONR7R45; -(CR51R53)q NR7COOR36;
-(CR51R53)q NR7COR38; -(CR51R53)q NR7CONR7R45;-(CR51R53)q NR7SO2R38;
-(CR51R53)q NR7SO2NR7R45;-(CR51R53)q COOR36; -(CR51R53)q CONR7R45;
-(CR51R53)q SO2NR7R45; -(CR51R53)t COR44; -(CR51R53)q SO2R38; -(CR51R53)t R39;
-(CR51R53)u R40; -(CR51R53)t R41; or -(CR51R53)t R44;
R38 is C1-24-alkyl; C2-24-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1-12-alkyl; or heteroaryl-C1-12-alkyl;
R39 is aryl; heteroaryl; -C6H2R3R4R46; or a group of one of the formulae R40 is a group of one of the formulae R41 is a group of one of the formulae R42 and R43 are independently defined as H; F; CF3; C1-24-alkyl; C2-24-alkenyl;
cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C1-12-alkyl; or heteroaryl-C1-12-alkyl;

R44 is H; C1-24-alkyl; C2-24-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1-12-alkyl; heteroaryl-C1-12-alkyl; or a group of one of the formulae R45 is H; C1-24-alkyl; C2-24-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1-12-alkyl; heteroaryl-C1-12-alkyl; an N-protecting group; -(CR51R53)r OR36;
-(CR51R53)r NR7R57; -(CR51R53)r OCONR7R57; -(CR51R53)r NR7CONR7R57;
-(CR51R53)r NR7COR38; -(CR51R53)r NR7SO2NR7R57; -(CR51R53)r NR7SO2R38;
-(CR51R53)q COOR36; -(CR51R53)q COR38; -(CR51R53)q SO2R38; -(CR51R53)q R39;
-(CR51R53)s R40; -(CR51R53)q R41; or -(CR51R53)s R44;
R46 is H; F; Cl; CF3; OCF3; OCHF2; NO2; CN; C1-24-alkyl; C2-24-alkenyl; C2-10-alkynyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C1-12-alkyl;
heteroaryl-C1-12-alkyl; -(CR51R53)q OR36; -(CR51R53)q SR36; -(CR51R53)q NR7R57;
-(CR51R53)q OCONR7R57; -(CR51R53)q NR7COOR36; -(CR51R53)q NR7COR38;
-(CR51R53)q NR7CONR7R45; -(CR51R53)q NR7SO2R38; -(CR51R53)q NR7SO2NR7R45;
-(CR51R53)q COOR36; -(CR51R53)q CONR7R45;-(CR51R53)q SO2NR7R45;
-(CR51R53)q COR38; -(CR51R53)q SO2R38; or -(CR51R53)q R44;

R47 is H; C1-24-alkyl; C2-24-alkenyl; C2-10-alkynyl; cycloalkyl;
heterocycloalkyl;
aryl; heteroaryl; aryl-C1-12-alkyl; heteroaryl-C1-12-alkyl; or -NR7R45;
R48 is H; C1-24-alkyl; C2-24-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1-12-alkyl; heteroaryl-C1-12-alkyl; an N-protecting group; -(CR51R53)r OR45;
-(CR51R53)r SR45; -(CR51R53)r NR7R45; -(CR51R53)r OCONR7R45;
-(CR51R53)r NR7COOR38; -(CR51R53)r NR7COR38; -(CR51R53)r NR7CONR7R45;
-(CR51R53)r NR7SO2R38; -(CR51R53)r NR7SO2NR7R45; -(CR51R53)q COOR36;
-(CR51R53)q CONR7R45; -(CR51R53)r SO2NR7R45; -(CR51R53)q COR38;
-(CR51R53)q SO2R38; or -(CR51R53)s R44;
R49 is H; C1-24-alkyl; C2-24-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1-12-alkyl; heteroaryl-C1-12-alkyl; -(CR51R53)q OR36; -(CR51R53)q SR36;
-(CR51R53)q NR7R45; -(CR51R53)q NR7COOR36; -(CR51R53)q NR7COR38;
-(CR51R53)q NR7SO2R38; -(CR51R53)q NR7CONR7R45; -(CR51R53)q COOR36;
-(CR51R53)q CONR7R45; -(CR51R53)q COR38; or -(CR51R53)q R44;
R50 is H; C1-24-alkyl; C2-6-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl; or an N-protecting group;
R51 and R53 are independently defined as H; F; CF3; C1-24-alkyl; C2-24-alkenyl;
cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C1-12-alkyl; heteroaryl-C1-12-alkyl;
-(CR42R43)t OR36; -(CR42R43)t NR7R57; -(CR42R43)t COOR36; or -(CR42R43)t CONR7R57;
R52 is H; CF3; C1-24-alkyl; C2-24-alkenyl; cycloalkyl; heterocycloalkyl; aryl;

heteroaryl; aryl-C1-12-alkyl; heteroaryl-C1-12-alkyl; -OR36; -NR7R57; -NR7COR38;
-NR7COOR36; -NR7SO2R38; -NR7CONR7R57; -COOR36; -CONR7R57;
-C(=NR7)NR7R57; -NR7C(=NR7)NR7R57; or a group of one of the formulae R54 is H; F; CF3; OCF3; OCHF2; NO2; CN; C1-24-alkyl; C2-24-alkenyl; C2-10-alkynyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C1-12-alkyl;
heteroaryl-C1-12-alkyl; ¨OR36; ¨NR7R57; ¨NR7COR38; ¨NR7SO2R38; ¨NR7CONR7R57; ¨COR38; or ¨SO2R38;
R55 is H; CF3; C1-24-alkyl; C2-24-alkenyl; C2-10-alkynyl; cycloalkyl;
heterocycloalkyl; aryl; heteroaryl; aryl-C1-12-alkyl; heteroaryl-C1-12-alkyl;
¨COOR36; or ¨CONR7R45;
R56 is H; F; CF3; C1-24-alkyl; C2-24-alkenyl; cycloalkyl; heterocycloalkyl;
aryl;
heteroaryl; aryl-C1-12-alkyl; heteroaryl-C1-12-alkyl; ¨(CR42R43)s OR36;
¨(CR42R43)s NR7R45; ¨(CR42R43)q COOR36; or ¨(CR42R43)q CONR7R45;
R57 is H; C1-24-alkyl; C2-24-alkenyl; cycloalkyl; aryl; aryl-C1-12-alkyl; or an N-protecting group;
taken together (R5 and R6); (R7 and R14); (R7 and R16); (R7 and R18); (R7 and R20); (R7 and R22); (R7 and R24); (R7 and R26); (R7 and R28); (R7 and R30);
(R7 and R35);
(R7 and R45); (R7 and R57); (R13 and R13); (R14 and R16); (R14 and R18); (R15 and R51);
(R19 and R51); (R20 and R22); (R20 and R24); (R26 and R28); (R26 and R30);
(R32 and R33);
(R42 and R43); or (R51 and R53) can form optionally substituted cycloalkyl or heterocycloalkyl moieties;
and the structural elements ¨NR7R35; or ¨NR44R45 can form one of the groups of the formulae T is CR54 or N;
Q is O; S; or NR35;
M is O; S; or NR7;
m is an integer of 0-8;
n is an integer of 0-1;
p is an integer of 0-4;
q is an integer of 0-4;
r is an integer of 2-4;
s is an integer of 1-4;
t is an integer of 0-2;
u is an integer of 1-2;
or a stereoisomer of such a compound; or a salt, solvate, clathrate, N-oxide, isotopically enriched or enantiomerically enriched version thereof.

2. A compound according to claim 1 wherein the Template A is selected from A B1 ¨A C1 ; A B1¨A C2; A B1¨A C3 ; A B1¨A C4; A B1¨A C5; A B1¨A C6; A B1¨A
C8;
A B1¨A C9; A B1¨A C11 ; A B1¨A C12; A B1¨A C13; A B1¨A C19; A31¨A C22; A B1¨A
C24;
A B1 ¨A C49 ; A B1¨A C51; A B2¨A C1; A B2¨A C2; A B2¨A C3; A B2¨A C4; A32¨A
C5; A B2¨A C11;
A B2¨A C12; A B2¨A C51; A B3¨A C1; A B3¨A C2; A B3¨A C3; A B3¨A C4; A B3¨A C5;
A B3¨A C11;
A B3¨A C12; A B4¨A C1 ; A B4¨A C2; A B4¨A C3; A B4¨A C4; A B4¨A C5; A B4¨A C6;
A B4¨A C11 ;
A B4¨A C12; A B4¨A C19 ; A B4¨A C22; A B4¨A C24 ; A B4¨A C49 ; A B4¨A C51; A
B4¨A C59 ;
A B5¨A C1; A B5¨A C2; A B5¨A C3; A B5¨A C4; A B5¨A C5; A B5¨A C11; A B5¨A C12;
A B5¨A C51;
A B5¨A C59; A B6¨A C1; A B6¨A C4; A B6¨A C8; A B6¨A C9; A B6¨A C11; A B6¨A
C13; A36¨A C16;
A B6¨A C18; A B6¨A C19; A B6¨A C20; A B6¨A C30; A B6¨A C31; A B6¨A C49; A B6¨A
C51;
A B9¨A C6; A B9¨A C49 ; A B10¨A C6; A B1 1 ¨A C6 ; A B1 2¨A C2; A B12¨A C5; A
B12¨A C11;

A B12¨A C12; A B13¨A C2; A B13¨A C5; A B13¨A C11 ; A B13¨A C12; A B13¨A C5; A
B13¨A C11;
A B 13¨A C12; A B14¨A C49 ; A B20¨A C2; A B20¨A C6; A B20¨A C49; A B23¨A C4; A
B23¨A C49;
A B26¨A C2; A B26¨A C5; A B26¨A C11; A B26¨A C12 ; A B40¨A C2; A B40¨A C5; A
B40¨A C11;
A B40¨A C12; A B45¨A C49; A B45¨A C52; A B45¨A C57; A B45¨A C58; A B45¨A C65;
A B45¨A C66; A B46¨A C57; A B46¨A C58; A B47¨A C58; A B49¨A C49; A B50¨A C57;
A B50¨A C58; A B50¨A B61; A B51¨A C49; A B51¨A C61; A B53¨A C2; A B53¨A C5; A
B53¨A C11;
A B53¨A C12 ; A B58¨A C2; A B58¨A C5; A B58¨A C11; A B58¨A C12 ; A B59¨A C2; A
B59¨A C5;
A B59¨A C11; A B59¨A C12 ; or A B59¨A C61;
the Modulator B is selected from B1; B4; B5; B6; B7; B8; B9 or B10;
the Bridge C is selected from C1 ; C2; or C3.
and wherein the Y-Z connectivity representing a divalent radical is selected from the group of V and W are representing independently a divalent radical selected from the group of or a stereoisomer of such a compound; or a salt, solvate, clathrate, N-oxide, isotopically enriched or enantiomerically enriched version thereof.

3. A compound according to claim 1 or 2 wherein R1 and R2 are independently defined as H; F; CI; Br; I; CF3; OCF3; OCHF2;
NO2; CN; C1-6-alkyl; C2-6-alkenyl; C2-6-alkynyl; cycloalkyl; heterocycloalkyl;

heteroaryl-C1-6-alkyl; ¨(CR32R33)q OR34; ¨(CR32R33)q SR34; ¨(CR32R33)q NR7R35;
¨(CR32R33)q OCONR7R35; ¨(CR32R33)q NR7COOR36; ¨(CR32R33)q NR7COR37;
¨(CR32R33)q NR7CONR7R35; ¨(CR32R33)q NR7SO2R38; ¨(CR32R33)q NR7SO2NR7R35;
¨(CR32R33)q COOR36; ¨(CR32R33)q CONR7R35;¨(CR32R33)q SO2NR7R35;
¨(CR32R33)q COR37; ¨(CR32R33)q SO2R38; ¨(CR32R33)q R39; ¨(CR32R33)q R40;
-(CR32R33)q R41; or ¨(CR32R33)q R44;
R3 and R4 are independently defined as H; F; CI; CF3; OCF3; OCHF2; NO2;
CN; C1-6-alkyl; cycloalkyl; C1-6-alkoxy or aryloxy;
R5 is H; CF3; C1-6-alkyl; or cycloalkyl;
R6 is H; CF3; C1-6-alkyl; C2-6-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl; aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl; ¨(CR32R33)q O R34;
¨(CR32R33)q SR34;
¨(CR32R33)q NR7R35; ¨(CR32R33)q OCONR7R35; ¨(CR32R33)q NR7COOR36;
¨(CR32R33)q NR7COR37; ¨(CR32R33)q NR7CONR7R35; ¨(CR32R33)q NR7SO2R38;
¨(CR32R33)q NR7SO2NR7R35;¨(CR32R33)q COOR36; ¨(CR32R33)q CONR7R35;
¨(CR32R33)q SO2NR7R35;¨(CR32R33)q COR37; ¨(CR32R33)q SO2R38; ¨(CR32R33)q R39;
¨(CR32R33)s R40; ¨(CR32R33)q R41; or ¨(CR32R33)q R44 ;
R7 is H; C1-6-alkyl; C2-6-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl; or an N-protecting group;
R8 and R9 are independently defined as H; CF3; C1-6-alkyl; cycloalkyl;
heterocycloalkyl;
R10, R11 and R12 are independently defined as H; C1-6-alkyl; or cycloalkyl;
R13 is C1-6-alkyl;

R14, R20 and R26 are independently defined as H; F; CF3; C1-6-alkyl; C2-6-alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C1-6-alkyl;
heteroaryl-C1-6-alkyl; ¨(CR32R33)q OR34; ¨(CR32R33)q SR34; ¨(CR32R33)q NR7R35;
¨(CR32R33)q OCONR7R35; ¨(CR32R33)q NR7COOR36; ¨(CR32R33)q NR7COR37;
¨(CR32R33)q NR7CONR7R35; ¨(CR32R33)q NR7SO2R38; ¨(CR32R33)q NR7SO2NR7R35;
¨(CR32R33)q COOR36; ¨(CR32R33)q CONR7R35;¨(CR32R33)q SO2NR7R35;
¨(CR32R33)q COR37; ¨(CR32R33)q SO2R38; ¨(CR32R33)q R39; ¨(CR32R33)s 40;
¨(CR32R33)q R41; or ¨(CR32R33)q R44;
R15, R17, R19, R21, R23, R25, R27, R29 and R31 are independently defined as H;
or C1-6-alkyl;
R16, R22 and R28 are independently defined as H; CF3; or C1-6-alkyl;
R18, R24 and R30 are independently defined as H; F; CF3; C1-6-alkyl; C2-6-alkenyl; cycloalkyl; heterocycloalkyl; aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl;

¨(CR32R33)q OR34; ¨(CR32R33)q NR7R35; ¨(CR32R33)q OCONR7R35;
¨(CR32R33)q NR7COOR36; ¨(CR32R33)q NR7COR37; ¨(CR32R33)q NR7CONR7R35;
¨(CR32R33)q NR7SO2R38; ¨(CR32R33)q NR7SO2NR7R35;¨(CR32R33)q COOR36;
¨(CR32R33)q CONR7R35; ¨(CR32R33)q SO2NR7R35; ¨(CR32R33)q COR37; or ¨(CR32R33)q R44;
R32 is H; F; CF3; C1-6-alkyl; C2-6-alkenyl; cycloalkyl; heterocycloalkyl;
aryl;
heteroaryl; aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl; ¨(CR42R51)q OR45;
¨(CR42R51)q SR45;
¨(CR42R51)q NR7R45; ¨(CR42R51)q OCONR7R45; ¨(CR42R51)q NR7COOR36;
¨(CR42R51)q NR7COR38;¨(CR42R51)q NR7CONR7R45; ¨(CR42R51)q NR7SO2R38;
¨(CR42R51)q NR7SO2NR7R45;¨(CR42R51)q COOR36; ¨(CR42R51)q CONR7R45;
¨(CR42R51)q SO2NR7R45;¨(CR42R51)q COR38; ¨(CR42R51)q SO2R38; ¨(CR42R51)q R39;
¨(CR42R51)s R40; ¨(CR42R51)q R41; or ¨(CR42R51)q R44;
R33 is H; or C1-6-alkyl;
R34 is H; C1-6-alkyl; C2-6-alkenyl; cycloalkyl; aryl; heteroaryl; aryl-C1-6-alkyl;
heteroaryl-C1-6-alkyl; ¨(CR42R51),OR45; ¨(CR42R51)r NR7R45;
¨(CR42R51),OCONR7R35;
¨(CR42R51)r NR7COOR36; ¨(CR42R51)r NR7COR38; ¨(CR42R51)r NR7CONR7R45;
¨(CR42R51)r NR7SO2R38; ¨(CR42R51)q COOR36; ¨(CR42R51)q CONR7R45;

¨(CR42R51)q SO2NR7R45; ¨(CR42R51)q COR38; ¨(CR42R51)q SO2R38; ¨(CR42R51)q R39;
¨(CR42R51)s R40; ¨(CR42R51)q R41; or ¨(CR42R51)q R44;
R35 is H; C1-6-alkyl; C2-6-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl; an N-protecting group; ¨(CR32R33)r OR45;
¨(CR32R33)r NR7R45; ¨(CR32R33)r OCONR7R45; ¨(CR32R33),NR7COOR36;
¨(CR32R33)r NR7COR37; ¨(CR32R33)r NR7CONR7R45; ¨(CR32R33)r NR7SO2R38;
¨(CR32R33)r NR7SO2NR7R45; ¨(CR32R33)q COOR38; ¨(CR32R33)q CONR7R45;
¨(CR32R33)q COR37; ¨(CR32R33)q SO2R38; ¨(CR32R33)q SO2NR7R50; ¨(CR32R33)q R39;

¨(CR32R33)s R40; ¨(CR32R33)q R41; or ¨(CR32R33)q R44;
R38 is H; C1-6-alkyl; cycloalkyl; aryl; aryl-C1-6-alkyl; or an O/S-protecting group;
R37 is C1-6-alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C1-6-alkyl;
heteroaryl-C1-6-alkyl; ¨(CR42R51)q OR45; ¨(CR42R51)q SR45; ¨(CR42R51)q NR7R45;
¨(CR42R51)s OCONR7R45; ¨(CR42R51)s NR7COOR36; ¨(CR42R51)q NR7COR44;
¨(CR42R51)s NR7CONR7R45;¨(CR42R51)s NR7SO2R38; ¨(CR42R51)s NR7SO2NR7R45;
¨(CR42R51)q COOR36; ¨(CR42R51)q CONR7R45;¨(CR42R51)q SO2NR7R45;
¨(CR42R51)t COR38; ¨(CR42R51)q SO2R38; ¨(CR42R51)t R38; ¨(CR42R51)u R40;
¨(CR42R51)t R41; or ¨(CR42R51)t R44;
R38 is C1-6-alkyl; C2-6alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl; aryl-C1-6-alkyl; or heteroaryl-C1-6-alkyl;
R42 and R43 are independently defined as H; F; CF3; C1-6-alkyl; C2-6-alkenyl;
cycloalkyl; heterocycloalkyl; aryl-C1-6-alkyl; or heteroaryl-C1-6-alkyl;
R44 is H; C1-6-alkyl; C2-6-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl; or a group of one of the formulae R45 is H; C1-6-alkyl; C2-6-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl; an N-protecting group; -(CR42R51),OR36;
-(CR42R51)r NR7R57; -(CR42R51)r OCONR7R57; -(CR42R51)r NR7CONR7R57;
-(CR42R51)r NR7COR38; -(CR42R51)r NR7SO2R38; -(CR42R51)r NR7SO2NR7R57;
-(CR42R51)q COOR36; -(CR42R51)q COR38; -(CR42R51)q SO2R33; -(CR42R51)q R39;
-(CR42R51)s R40; -(CR42R51)q R41; or -(CR42R51)s R44;
R46 is H; F; CI; CF3; OCF3; OCHF2; NO2; CN; C1-6-alkyl; C2-6-alkenyl; C2-6-alkynyl; cycloalkyl; heterocycloalkyl; aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl;
-(CR42R51)q OR36; -(CR42R51)q SR36; -(CR42R51)q NR7R57; -(CR42R51)q OCONR7R57;

-(CR42R51)q NR44COOR36; -(CR42R51)q NR7COR38; -(CR42R51)q NR7CONR7R45;
-(CR42R51)q N R7SO2R38; -(CR42R51)q NR7SO2NR7R45;-(CR42R51)q COOR36;
-(CR42R51)q CONR7R45;-(CR42R51)q SO2NR7R45; -(CR42R51)q COR38;
-(CR42R51)q SO2R38; or -(CR42R51)q R44;
R47 is H; C1-6-alkyl; C2-6-alkenyl; C2-6-alkynyl; cycloalkyl;
heterocycloalkyl; aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl; or -NR7R45;
R48 is H; C1-6-alkyl; C2-6-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl; an N-protecting group; -(CR42R51),OR45;
-(CR42R51)r SR45; -(CR42R51)r NR7R45; -(CR42R51)r OCONR7R45;
-(CR42R51)r NR7COOR36; -(CR42R51)r NR7COR38; -(CR42R51),NR7CONR7R45;
-(CR42R51)r NR7SO2R38; -(CR42R51),NR7SO2NR7R45;-(CR42R51)q COOR36;

-(CR42R51)q CONR7R45; -(CR42R51)r SO2NR7R45; -(CR42R51)q COR38;
-(CR42R51)q SO2R38; or -(CR42R51)s R44;
R49 is H; C1-6-alkyl; C2-6-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl; -(CR42R51)q OR36; -(CR42R51)q SR36;
-(CR42R51)q NR7R45; -(CR42R51)q NR7COOR36; -(CR42R51)q NR7COR38;
-(CR42R51)q NR7SO2R38; -(CR42R51)q NR7CONR7R45; -(CR42R51)q COOR36;
-(CR42R51)q CONR7R45; -(CR42R51)q COR38; or -(CR42R51)q R44;
R50 is H; C1-6-alkyl; C2-6-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl; or an N-protecting group;
R51 and R53 are independently defined as H; F; CF3; C1-6-alkyl; C2-6-alkenyl;
cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl;
-(CR42R43)t OR36; -(CR42R43)t NR7R57; -(CR42R43)t COOR36; or -(CR42R43)t CONR7R57;
R52 is H; CF3; C1-6-alkyl; C2-6-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl; aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl; -OR36; -NR7R57; -NR7COR38;
-NR7COOR36; -NR7SO2R38; -NR7CONR7R57; -COOR36; -CONR7R57;
-C(=NR7)NR7R57; -NR7C(=NR7)NR7R57; or a group of one of the formulae R54 is H; F; CF3; OCF3; OCHF2; NO2; CN; C1-6-alkyl; C2-6-alkenyl; C2-6-alkynyl;
cycloalkyl; heterocycloalkyl; aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl; ¨OR36;
¨NR7R57;
¨NR7COR38; ¨N R7SO2R38; ¨N R7CONR7R57; ¨COR38; or ¨SO2R38;
R55 is H; CF3; C1-6-alkyl; C2-6-alkenyl; C2-6-alkynyl; cycloalkyl;
heterocycloalkyl;
aryl; heteroaryl; aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl; ¨COOR36; or ¨CONR7R45;
R56 is H; F; CF3; C1-6-alkyl; C2-6-alkenyl; cycloalkyl; heterocycloalkyl;
aryl;
heteroaryl; aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl; ¨(CR42R43)s OR36;
¨(CR42R43)s NR7R45;
¨(CR42R43)q COOR36; or ¨(CR42R43)q CONR7R45;
R57 is H; C1-6-alkyl; C2-6-alkenyl; cycloalkyl; aryl-C1-6-alkyl; or an N-protecting group;
or a stereoisomer of such a compound; or a salt, solvate, clathrate, N-oxide, isotopically enriched or enantiomerically enriched version thereof.

4. A compound according to claim 1, 2 or 3 wherein the Template A is selected from A B1¨A C1; A B1¨A C4; A B1¨A C6; A B1¨A C8; A B1¨A C9; A B1¨A C11; A B1¨A C13;

A B1¨A C19 ; A B1 ¨A C22; A B1 ¨A C24; A B1¨A C49; A B1¨A C51; A B2¨A C4; A
B2¨A C51;
A B4¨A C1; A B4¨A C4; A B4¨A C6; A B4¨A C19 ; A B4¨A C22 ; A B4¨A C24 ; A B4¨A
C49;
A B4¨A C51; A B4¨A C59; A B5¨A C51; A B5¨A C59; A B6¨A C1; A B6¨A C4; A B6¨A
C8; A B6¨A C9;
A B6¨A C11; A B6¨A C13; A B6¨A C16 ; A B6¨A C18 ; A B6¨A C19 ; A B6¨A C20; A
B6¨A C30;
A B6¨A C31; A B6¨A C49; A B6¨A C51; A B9¨A C6; A B9¨A C49; AB14-A C49; A B20¨A
C6;
A B20¨A C49; A B23¨A C4; A B23¨A C49; A B45¨A C49; A B45¨A C52; A B45¨A C57;
A B45¨A C58; A B45¨A C65; A B45¨A C66; A B46¨A C57; A B46¨A C58; A B49¨A C49;
A B50¨A C57; A B50¨A C58; A B50¨A C61; A B51¨A C49; A B51¨A C61; or A B59¨A
C61;
the Modulator B is selected from B1; B4; B5; B6; or B7;
and wherein R1 and R2 are independently defined as H; F; CI; Br; I; CF3; OCF3; OCHF2;
NO2; CN; C1-6-alkyl; C2-6-alkenyl; C2-6-alkynyl; cycloalkyl; heterocycloalkyl;
aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl; -(CR32R33)q OR34; -(CR32R33)q SR34; -(CR32R33)q NR7R35;
-(CR32R33)q OCONR7R35; -(CR32R33)q NR7COOR36; -(CR32R33)q NR7COR37;
-(CR32R33)q NR7CONR7R35; -(CR32R33)q NR7SO2R38; -(CR32R33)q COOR36;
-(CR32R33)q CONR7R35; -(CR32R33)q SO2NR7R35; -(CR32R33)q COR37; -(CR32R33)q R39;
-(CR32R33)q R40; -(CR32R33)q R41; or -(CR32R33)q R44;
R3 and R4 are independently defined as H; F; CI; CF3; OCF3; OCHF2; NO2;
CN; C1-6-alkyl; or C1-6-alkoxy;
R5 is H; CF3; or C1-6-alkyl;
R6 is H; CF3; C1-6-alkyl; C2-6-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl; aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl; -(CR32R33)q OR34; -(CR32R33)q SR34;
-(CR32R33)q NR7R35; -(CR32R33)q OCONR7R35; -(CR32R33)q NR7COOR36;
-(CR32R33)q NR7COR37; -(CR32R33)q NR7CONR7R35; -(CR32R33)q NR7SO2R38;
-(CR32R33)q COOR36; -(CR32R33)q CONR7R35; -(CR32R33)q SO2NR7R35;
-(CR32R33)q COR37; -(CR32R33)q R39; -(CR32R33)s R40; -(CR32R33)q R41; or -(CR32R33)q R44;
R14, R20 and R26 are independently defined as H; F; CF3; C1-6-alkyl; C2-6-alkenyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C1-6-alkyl;
heteroaryl-C1-6-alkyl; -(CR32R33)q OR34; -(CR32R33)q SR34; -(CR32R33)q NR7R35;
-(CR32R33)q OCONR7R35; -(CR32R33)q NR7COOR36; -(CR32R33)q NR7COR37;
-(CR32R33)q NR7CONR7R35; -(CR32R33)q NR7SO2R38; -(CR32R33)q COOR36;
-(CR32R33)q CONR7R35; -(CR32R33)q SO2NR7R35; -(CR32R33)q COR37; -(CR32R33)q R39;
-(CR32R33)s R40; -(CR32R33)q R41; or -(CR32R33)q R44;
R18, R24 and R30 are independently defined as H; F; CF3; C1-6-alkyl; C2-6-alkenyl; cycloalkyl; heterocycloalkyl; aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl;

-(CR32R33)p OR34; -(CR32R33)q NR7R35; -(CR32R33)q OCONR7R35;
-(CR32R33)q NR7COOR36; -(CR32R33)q NR7COR37; -(CR32R33)q NR7CONR7R35;
-(CR32R33)q NR7SO2R38; -(CR32R33)q COOR36; -(CR32R33)q CONR7R35;
-(CR32R33)q COR37; or -(CR32R33)q R44;

R32 is H; F; CF3; C1-6-alkyl; C2-6-alkenyl; cycloalkyl; heterocycloalkyl;
aryl;
heteroaryl; aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl; -(CR42R43)q OR45; -(CR42R43)q SR45;
-(CR42R43)q NR7R45; -(CR42R43)q NR7COOR36; -(CR42R43)q NR7COR38;
-(CR42R43)q COOR36; -(CR42R43)q CONR7R45; -(CR42R43)q COR38; -(CR42R43)q R39;
-(CR42R43)s R40; -(CR42R43)q R41; or -(CR42R43)q R44;
R33 is H; or C1-6-alkyl;
R34 is H; C1-6-alkyl; C2-6-alkenyl; cycloalkyl; aryl; heteroaryl; aryl-C1-6-alkyl;
-(CR42R43)r OR45; -(CR42R43)r NR7R45; -(CR42R43)r OCONR7R35;
-(CR42R43)r NR7COOR36; -(CR42R43)r NR7COR38; -(CR42R43)r NR7CONR7R45;
-(CR42R43)r NR7SO2R38; -(CR42R43)q COOR38; -(CR42R43)q CONR7R48;
-(CR42R43)q COR38; -(CR42R43)q R39; -(CR42R43)s R40; -(CR42R43)q R41; or -(CR42R43)q R44;
R35 is H; C1-6-alkyl; C2-6-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl; an N-protecting group; -(CR32R33)r OR45;
-(CR32R33)r NR7R45; -(CR32R33)r OCONR7R45; -(CR32R33)r NR7COOR36;
-(CR32R33)r NR7COR37; -(CR32R33)r NR7CONR7R50; -(CR32R33)r NR7SO2R38;
-(CR32R33)q COOR36; -(CR32R33)q CONR7R45; -(CR32R33)q COR38; -(CR32R33)q R39;
-(CR32R33)s R40; -(CR32R33)q R41; or -(CR32R33)q R44;
R36 is H; C1-6-alkyl; cycloalkyl; aryl; aryl-C1-6-alkyl; or an O/S-protecting group;
R37 is C1-6-alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C1-6-alkyl;
heteroaryl-C1-6-alkyl; -(CR42R43)q OR45; -(CR42R43)q SR45; -(CR42R43)q NR7R45;
-(CR42R43)s OCONR7R45; -(CR42R43)s NR7COOR36; -(CR42R43)s NR7COR44;
-(CR42R43)s NR7CONR7R45; -(CR42R43)t NR7SO2R38; -(CR42R43)q COOR36;
-(CR42R43)q CONR7R45; -(CR42R43)t COR38; -(CR42R43)t R39; -(CR42R43)u R40;
-(CR42R43)t R41; or -(CR42R43)t R44;
R45 is H; C1-6-alkyl; C2-6-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl; an N-protecting group; -(CR42R43)r OR36;
-(CR42R43)r NR7R57; -(CR42R43)r OCONR7R57; -(CR42R43)r NR7CONR7R57;
-(CR42R43)r NR7COR38; -(CR42R43)r NR7SO2R38; -(CR42R43)q COOR36;

-(CR42R43)q COR38; -(CR42R43)q R39; -(CR42R43)s R40-; -(CR42R43)q R41; or -(CR42R43)s R44;
R46 is H; F; Cl; CF3; OCF3; OCHF2; NO2; CN; C1-6-alkyl; C2-6-alkenyl; C2-6-alkynyl; cycloalkyl; heterocycloalkyl; aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl;

-(CR42R43)q OR36; -(CR42R43)q NR7R57; -(CR42R43)q NR7COR38; -(CR42R43)q COOR36;
-(CR42R43)q CONR7R45; -(CR42R43)q SO2NR7R45; -(CR42R43)q COR38; or -(CR42R43)q R44;
R47 is H; C1-6-alkyl; C2-6-alkenyl; C2-6-alkynyl; cycloalkyl;
heterocycloalkyl; aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl; or -NR7R45.
R48 is H; C1-6-alkyl; C2-6-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl; an N-protecting group; -(CR42R43)r OR45;
-(CR42R43)r SR45; -(CR42R43)r NR7R45; -(CR42R43)r OCONR7R45;
-(CR42R43)r NR7COOR36; -(CR42R43)r NR7COR38; -(CR42R43)r NR7CONR7R45;
-(CR42R43)r NR7SO2R38; -(CR42R43)q COOR36; -(CR42R43)q CONR7R45;
-(CR42R43)q COR38; or -(CR42R43)s R44;
R49 is H; C1-6-alkyl; C2-6-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl; -(CR42R43)q OR36; -(CR42R43)q NR7R45;
-(CR42R43)q NR7COR38; -(CR42R43)q NR7SO2R38; -(CR42R43)q COOR36;
-(CR42R43)q CONR7R45; -(CR42R43)q COR38; or -(CR42R43)q R44;
R50 is H; C1-6-alkyl; C2-6-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl; or an N-protecting group.
R51 and R53 are independently defined as H; F; CF3; C1-6-alkyl; C2-6-alkenyl;
cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl;
-(CR42R43)t OR36; -(CR42R43)t NR7R57; -(CR42R43)t COOR36; or -(CR42R43)t CONR7R57;
R54 is H; F; CF3; OCF3; OCHF2; NO2; CN; C1-6-alkyl; C2-6-alkenyl; C2-6-alkynyl;
cycloalkyl; heterocycloalkyl; aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl; -OR36; -NR7R57;
-NR7COR38; -NR7SO2R38; -NR7CONR7R57; -COR38; or -SO2R38;

R55 is H; CF3; C1-6-alkyl; C2-6-alkenyl; C2-6-alkynyl; cycloalkyl;
heterocycloalkyl;
aryl; heteroaryl; aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl; -COOR36; or -CONR7R45;
R56 is H; F; CF3; C1-5-alkyl; C2-6-alkenyl; cycloalkyl; heterocycloalkyl;
aryl;
heteroaryl; aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl; -(CR42R43)s OR36; -(CR42R43)s NR7R45;
-(CR42R43)q COOR36; or -(CR42R43)q CONR7R45.
or a stereoisomer of such a compound; or a salt, solvate, clathrate, N-oxide, isotopically enriched or enantiomerically enriched version thereof.

5. A compound according to any of claims 1, 2, 3 or 4 wherein the Template A is selected from A B1-A C1; A B1-A C4; A B1-A C19; A B2-A C4; A B4-A C1; A B4-A C4; A B4-A C19;

A B4-A C59; A B5-A C51; A B5-A C59; A B6-A C31; A B9-A C6; or A B46-A C58;
and wherein R3 and R4 are independently defined as H; F; CF3; OCF3; OCHF2; CN; or C1-6-alkoxy;
R5 is H; CF3; or C1-6-alkyl;
R33 is H; or C1.6-alkyl;
R46 is H; F; Cl; CF3; OCF3; OCHF2; NO2; CN; C1-6-alkyl; C2-6-alkenyl; C2-6-alkynyl; cycloalkyl; heterocycloalkyl; aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl;
or -(CR42R43)q R44;
R47 is H; C1-6-alkyl; C2-6-alkenyl; C2-6-alkynyl; cycloalkyl;
heterocycloalkyl; aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl; or -NR7R45;
R49 is H; C1-6-alkyl; C2-6-alkenyl; cycloalkyl; heterocycloalkyl; aryl;
heteroaryl;
aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl; or -(CR42R43)q R44;

R51 and R53 are independently defined as H; F; CF3; C1-6-alkyl; C2-6-alkenyl;
cycloalkyl; heterocycloalkyl; aryl; heteroaryl; aryl-C1-6-alkyl; heteroaryl-C1-

6-alkyl;
-(CR42R43)t OR36; -(CR42R43)t NR7R57; -(CR42R43)t COOR36; or -(CR42R43)t CONR7R57;
R54 is H; F; CF3; OCF3; OCHF2; NO2; CN; C1-6-alkyl; C2-6-alkenyl; C2-6-alkynyl;
cycloalkyl; heterocycloalkyl; aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl; -OR36; -NR7R57;
-NR7COR38; -NR7SO2R38; -NR7CONR7R57; -COR38; or -SO2R38;
R55 is H; CF3; C1-6-alkyl; C2-6-alkenyl; C2-6-alkynyl; cycloalkyl;
heterocycloalkyl;
aryl; heteroaryl; aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl; -COOR36; or -CONR7R45;
R56 is H; F; CF3; C1-6-alkyl; C2-6-alkenyl; cycloalkyl; heterocycloalkyl;
aryl;
heteroaryl; aryl-C1-6-alkyl; heteroaryl-C1-6-alkyl; -(CR42R43)s OR36; -(CR42R43)s NR7R45;
-(CR42R43)q COOR36; or -(CR42R43)q CONR7R45;
or a stereoisomer of such a compound; or a salt, solvate, clathrate, N-oxide, isotopically enriched or enantiomerically enriched version thereof.
6. A compound according to any of claim 1 to claim 5 wherein the Bridge C is represented by and wherein C AA is an amino acid selected from Ala L-Alanine;
Arg L-Arginine;
Asn L-Asparagine;
Asp L-Aspartic acid;
Cys L-Cysteine;
Glu L-Glutamic acid;
Gln L-Glutamine;
Gly Glycine;
His L-Histidine;

Ile L-Isoleucine;
Leu L-Leucine;
Lys L-Lysine;
Met L-Methionine;
Phe L-Phenylalanine;
Pro L-Proline;
Ser L-Serine;
Thr L-Threonine;
Trp L-Tryptophan;
Tyr L-Tyrosine;
Val L-Valine;
Apa 3-Amino-propanoic acid;
H-.beta.3-HAla-OH (3S)-3-Amino-butyric acid;
H-.beta.3-HVal-OH (3R)-3-Amino-4-methyl-valeric acid;
H-.beta.3-Hlle-OH (3R, 4S)-3-Amino-4-methyl-hexanoic acid;
H-.beta.3-HLeu-OH (3S)-3-Amino-5-methyl-hexanoic acid;
H-.beta.3-HMet-OH (3S)-3-Amino-5-methylthio pentanoic acid;
H-.beta.3-HTyr-OH (3S)-3-Amino-4-(4'-hydroxyphenyI)-butyric acid;
H-.beta.3-HHis-OH (3S)-3-Amino-4-(imidazole-4'-yI)-butyric acid;
H-.beta.3-HPhe-OH (3S)-3-Amino-4-phenyl butyric acid;
H-.beta.3-HTrp-OH (3S)-3-Amino-4-(indol-3'-yl)-butyric acid;
H-.beta.3-HSer-OH (3R)-3-Amino-4-hydroxy-butyric acid;
H-.beta.3-HAsp-OH 3-Amino-pentanedioic acid;
H-.beta.3-HGlu-OH (3S)-3-Amino-hexanedioic acid;
H-.beta.3-HLys-OH (3S)-3,7-Diamino-heptanoic acid;
H-.beta.3-HArg-OH (3S)-3-Amino-6-guanidino-hexanoic-acid;
H-.beta.3-HCys-OH (3R)-3-Amino-4-mercapto-butyric acid;
H-.beta.3-HAsn-OH (3S)-3-Amino-4-carbamoyl-butyric acid;
H-.beta.3-HGln-OH (3S)-3-Amino-5-carbamoyl-pentanoic acid;
H-.beta.3-HThr-OH (3R,4R)-3-Amino-4-hydroxy-pentanoic acid;
Gaba 4-Amino-butyric acid;
H-.gamma.4-DiHAla-OH (4S)-4-Amino-pentanoic acid;
H-.gamma.4-DiHVal-OH (4R)-4-Amino-5-methyl-hexanoic acid;
H-.gamma.4-DiHIle-OH (4R, 5S)-4-Amino-5-methyl-heptanoic acid;
H-.gamma.4-DiHLeu-OH (4R)-4-Amino-6-methyl-heptanoic acid;

H-y4-DIHMet-OH (4R)-4-Amino-6-methylthio-hexanoic acid;
H-y4-DiHTyr-OH (4R)-4-Amino-5-(4'-hydroxyphenyl)-pentanoic acid;
H-y4-DiHHis-OH (4R)-4-Amino-5-(imidazole-4'-yl)-pentanoic acid;
H-y4-DiHPhe-OH (4R)-4-Amino-5-phenyl-pentanoic acid;
H-y4-DiHTrp-OH (4R)-4-Amino-5-(indol-3'-yl)-pentanoic acid;
H-y4-DiHSer-OH (4R)-4-Amino-5-hydroxy-pentanoic acid;
H-y4-DiHAsp-OH (4R)-4-Amino-hexanedioic acid;
H-y4-DiHGIu-OH 4-Amino-heptanedioic acid;
H-y4-DiHLys-OH (4S)-4,8-Diamino-octanoic acid;
H-y4-DiHArg-OH (4S)-4-Amino-7-guanidino-heptanoic-acid;
H-y4-DiHCys-OH (4R)-4-Amino-5-mercapto-pentanoic acid;
H-y4-DiHAsn-OH (4R)-4-Amino-5-carbamoyl-pentanoic acid;
H-y4-DiHGln-OH (3S)-3-Amino-5-carbamoyl-hexanoic acid;
H-y4-DiHThr-OH (4R, 5R)-4-Amino-5-hydroxy-hexanoic acid;
Cit L-Citrulline;
Orn L-Ornithine;
tBuA L-t-Butylalanine;
Sar Sarcosine;
Pen L-Penicillamine;
tBuG L-tert.-Butylglycine;
4AmPhe L-para-Aminophenylalanine;
3AmPhe L-meta-Aminophenylalanine;
2AmPhe L-ortho-Aminophenylalanine;
Phe(mC(NH2)=NH) L-meta-Amidinophenylalanine;
Phe(pC(NH2)=NH) L-para-Amidinophenylalanine;
Phe(mNHC(NH2)=NH) L-meta-Guanidinophenylalanine;
Phe(pNHC(NH2)=NH) L-para-Guanidinophenylalanine;
2Pal (2S)-2-Amino-3-(pyridine-2'-yI)-propionic acid;
4Pal (2S)-2-Amino-3-(pyridine-4)-propionic acid;
Phg L-Phenylglycine;
Cha L-Cyclohexylalanine;
C4al L-3-Cyclobutylalanine;
C5al L-3-Cyclopentylalanine;
Nle L-Norleucine;
2-Nal L-2-Naphthylalanine;

1-Nal L-1-Naphthylalanine;
4CIPhe L-4-Chlorophenylalanine;
3CIPhe L-3-Chlorophenylalanine;
2CIPhe L-2-Chlorophenylalanine;
3,4Cl2Phe L-3,4-Dichlorophenylalanine;
4FPhe L-4-Fluorophenylalanine;
3FPhe L-3-Fluorophenylalanine;
2FPhe L-2-Fluorophenylalanine;
Thi L-3-2-Thienylalanine;
Tza L-2-Thiazolylalanine;
Mso L-Methionine sulfoxide;
AcLys N-Acetyllysine;
Dap 2,3-Diaminopropionic acid;
Dab 2,4-Diaminobutyric acid;
Dbu (2S)-2,3-Diamino-butyric acid;
Abu .gamma.-Aminobutyric acid (GABA);
Aha .epsilon.-Aminohexanoic acid;
Aib .alpha.-Aminoisobutyric acid;
ACC 1-Amino cyclopropane carboxylic acid;
ACBC 1-Amino cyclobutane carboxylic acid;
ACPC 1-Amino cyclopentane carboxylic acid;
1-ACHC 1-Amino cyclohexane carboxylic acid;
2-ACHC 2-Amino cyclohexane carboxylic acid;
3-ACHC 3-Amino cyclohexane carboxylic acid;
4-ACHC 4-Amino cyclohexane carboxylic acid;
Y(BzI) L-O-Benzyltyrosine;
H(Bzl) (3S)-2-Amino-3-(1'-benzylimidazole-4'-yl)-propionic acid;
Bip L-(4-phenyl)phenylalanine;
S(BzI) L-O-Benzylserine;
T(BzI) L-O-Benzylthreonine;
alloT (2S, 3S)-2-Amino-3-hydroxy-butyric acid;
(2S, 3R)-2-Amino-3-hydroxy-4-methyl-pentanoic Leu3OH acid;
hAla L-Homo-alanine;

hArg L-Homo-arginine;
hCys L-Homo-cysteine;
hGlu L-Homo-glutamic acid;
hGln L-Homo-glutamine;
hHis L-Homo-histidine;
hile L-Homo-isoleucine;
hLeu L-Homo-leucine;
hNie L-Homo-norleucine;
hLys L-Homo-lysine;
hMet L-Homo-Methionine;
hPhe L-Homo-phenylalanine;
hSer L-Homo-serine;
hThr L-Homo-threonine;
hTrp L-Homo-tryptophan;
hTyr L-Homo-tyrosine;
hVal L-Homo-valine;
hCha L-Homo-cyclohexylalanine;
Bpa L-4-Benzoylphenylalanine;
OctG L-Octylglycine;
(3S)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic Tic acid;
(1S)-1,2,3,4-Tetrahydroisoquinoline-1-carboxylic Tiq acid;
(2S, 3aS, 7aS)-1-Octahydro-1H-indole-2-carboxylic Oic acid;
4AmPyrr1 (2S, 4S)-4-Amino-pyrrolidine-2-carboxylic acid;
4AmPyrr2 (2S, 4R)-4-Amino-pyrrolidine-2-carboxylic acid;
4PhePyrr1 (2S, 4R)-4-Phenyl-pyrrolidine-2-carboxylic acid;
4PhePyrr2 (2S, 4S)-4-Phenyl-pyrrolidine-2-carboxylic acid;
5PhePyr1 (28, 5R)-5-Phenyl-pyrrolidine-2-carboxylic acid;
5PhePyrr2 (2S, 5S)-5-Phenyl-pyrrolidine-2-carboxylic acid;
4Hyp1 (4S)-L-Hydroxyproline;
4Hyp2 (4R)-L-Hydroxyproline;
4Mp1 (4S)-L-Mercaptoproline;
4Mp2 (4R)-L-Mercaptoproline;

Pip L-Pipecolic acid;
H--.beta.3-HCit-OH (3S)-3-Amino-6-carbamidyl-hexanoic acid;
H--.beta.3-HOrn-OH (3S)-3,6-Diamino-hexanoic acid;
H--.beta.3-HtBuA-OH (3S)-3-Amino-5,5-dimethyl-hexanoic acid;
H--.beta.3-HSar-OH N-Methyl-3-amino-propionic acid;
H--.beta.3-HPen-OH (3R)-3-Amino-4-methyl-4-mercapto-pentanoic acid;
H--.beta.3-HtBuG-OH (3R)-3-Amino-4,4-dimethyl-pentanoic acid;
H-.beta.3-H4AmPhe-OH (3S)-3-Amino-4-(4'-aminophenyl)-butyric acid;
H-.beta.3-H3AmPhe-OH (3S)-3-Amino-4-(3'-aminophenyI)-butyric acid;
H-.beta.3-H2AmPhe-OH (3S)-3-Amino-4-(2'-aminophenyl)-butyric acid;
H-.beta.3-HPhe(mC(NH2)=NH)-OH (3S)-3-Amino-4-(3'-amidinophenyl)-butyric acid;
H-.beta.3-HPhe(pC(NH2)=NH)-OH (3S)-3-Amino-4-(4'-amidinophenyI)-butyric acid;
H-.beta.3-HPhe(mNHC(NH2)=NH)-OH (3S)-3-Amino-4-(3'-guanidinophenyl)-butyric acid;
H-.beta.3-HPhe(pNHC(NH2)=NH)-OH (3S)-3-Amino-4-(4'-guanidino-phenyI)-butyric acid;
H-.beta.3-H2Pal-OH (3S)-3-Amino-4-(pyridine-2'-yl)-butyric acid;
H-.beta.3-H4Pal-OH (3S)-3-Amino-4-(pyridine-4'-yl)-butyric acid;
H-.beta.3-HPhg-OH (3R)-3-Amino-3-phenyl-propionic acid;
H-.beta.3-HCha-OH (3S)-3-Amino-4-cyclohexyl-butyric acid;
H-.beta.3-HC4al-OH (3S)-3-Amino-4-cyclobutyl-butyric acid;
H-.beta.3-HC5al-OH (3S)-3-Amino-4-cyclopentyl-butyric acid;
H-.beta.3-HNIe-OH (3S)-3-Amino-heptanoic acid;
H-.beta.3-H2Nal-OH (3S)-3-Amino-4-(2'-naphthyl)-butyric acid;
H-.beta.3-H1 Nal-OH (3S)-3-Amino-4-(1'-naphthyl)-butyric acid;
H-.beta.3-H4CIPhe-OH (3S)-3-Amino-4-(4'-chlorophenyI)-butyric acid;
H-.beta.3-H3CIPhe-OH (3S)-3-Amino-4-(3'-chlorophenyl)-butyric acid;
H-.beta.3-H2CIPhe-OH (3S)-3-Amino-4-(2'-chlorophenyI)-butyric acid;
H-.beta.3-H3,4Cl2Phe-OH (3S)-3-Amino-4-(3',4'-dichlorophenyI)-butyric acid;
H-.beta.3-H4FPhe-OH (3S)-3-Amino-4-(4'-fluorophenyl)-butyric acid;
H-.beta.3-H3FPhe-OH (3S)-3-Amino-4-(3'-fluorophenyI)-butyric acid;
H-.beta.3-H2FPhe-OH (3S)-3-Amino-4-(2'-fluorophenyl)-butyric acid;
H-.beta.3-HThi-OH (3R)-3-Amino-4-(2'-thienyl)-butyric acid;
H-.beta.3-HTza-OH (3R)-3-Amino-4-(2'-thiazolyI)-butyric acid;
H-.beta.3-HMso-OH (3R)-3-Amino-4-methylsulfoxyl-butyric acid;

H-.beta.3-HAcLys-OH (3S)-7-Acetylamino-3-amino-heptanoic acid;
H.-.beta.3-HDpr-OH (3R)-3,4-diamino-butyric acid;
H-.beta.3-HA2Bu-OH (3S)-3,5-Diamino-pentanoic acid;
H-.beta.3-HDbu-OH (3R)-3,4-Diamino-pentanoic acid;
H-.beta.3-HAib-OH Amino-dimethyl acetic acid;
H-.beta.3-HCyp-OH 1-Amino-cyclopentane-1-yl-acetic acid;
H-.beta.3-HY(Bzl)-OH (3S)-3-Amino-4-(4'-benzyloxyphenyl)-butyric acid;
(3S)-3-Amino-4-(1'-benzylimidazole-4'-yl)-butyric H-.beta.3-HH(Bzl)-OH acid;
H-.beta.3-HBip-OH (3S)-3-Amino-4-biphenylyl-butyric acid;
H-.beta.3-HS(Bzl)-OH (3S)-3-Amino-4-(benzyloxy)-butyric acid;
H-.beta.3-HT(Bzl)-OH (3R, 4R)-3-Amino-4-benzyloxy-pentanoic acid;
H-.beta.3-HalloT-OH (3R, 4S)-3-Amino-4-hydroxy-pentanoic acid;
H-.beta.3-HLeu3OH-OH (3R, 4R)-3-Amino-4-hydroxy-5-methyl-hexanoic acid;
H-.beta.3-HhAla-OH (3S)-3-Amino-pentanoic acid;
H-.beta.3-HhArg-OH (3S)-3-Amino-7-guanidino-heptanoic acid;
H-.beta.3-HhCys-OH (3R)-Amino-5-mercapto-pentanoic acid;
H-.beta.3-HhGlu-OH (3S)-3-Amino-heptanedioic acid;
H-.beta.3-HhGln-OH (3S)-3-Amino-6-carbamoyl hexanoic acid;
H-.beta.3-HhHis-OH (3S)-3-Amino-5-(imidazole-4'-yl)-pentanoic acid;
H-.beta.3-HhIle-OH (3S, 5S)-3-Amino-5-methyl-heptanoic acid;
H-.beta.3-HhLeu-OH (3S)-3-Amino-6-methyl-heptanoic acid;
H-.beta.3-HhNle-OH (3S)-3-Amino-octanoic acid;
H-.beta.3-DiAoc-OH (3S)-3,8-Diamino-octanoic acid;
H-.beta.3-HhMet-OH (3S)-3-Amino-6-methylthio-hexanoic acid;
H-.beta.3-HhPe-OH (3S)-3-Amino-5-phenyl-pentanoic acid;
H-.beta.3-HhSer-OH (3S)-3-Amino-5-hydroxy-pentanoic acid;
H-.beta.3-HhThr-OH (3S, 5R)-3-Amino-5-hydroxy-hexanoic acid;
H-.beta.3-HhTrp-OH (3S)-3-Amino-5-(indol-3'-yl)-pentanoic acid;
H-.beta.3-HhThr-OH (3S)-3-Amino-5-(4'-hydroxyphenyl)-pentanoic acid;
H-.beta.3-HhCha-OH (3S)-3-Amino-5-cyclohexyl-pentanoic acid;
H-.beta.3-HBpa-OH (3S)-3-Amino-4-(4'-benzoylphenyl)-butyric acid;
H-.beta.3-HOctG-OH (3S)-3-Amino-undecanoic acid;
H-.beta.3-HNIe-OH (3S)-3-Amino-heptanoic acid;
H-.beta.3-HTic-OH (3S)-1,2,3,4-Tetrahydroisoquinoline-3-yl-acetic acid;

H-.beta.3-HTiq-OH (1S)-1,2,3,4-Tetrahydroisoquinoline-1-acetic acid;
(2S, 3aS, 7aS)-1-Octahydro-1H-indole-2-yl-acetic H-.beta.3-HOic-OH
acid;
H-.beta.3-H4AmPyrr1 -OH (2S, 4S)-4-Amino-pyrrolidine-2-acetic acid;
H-.beta.3-H4AmPyrr2-OH (2S, 4R)-4-Amino-pyrrolidine-2-acetic acid;
H-.beta.3-H4PhePyrr1-OH (2S, 4R)-4-Phenyl-pyrrolidine-2-acetic acid;
H-.beta.3-H4PhePyrr2-OH (2S, 4S)-4-Phenyl-pyrrolidine-2-acetic acid;
H-.beta.3-H5PhePyrr1-OH (2S, 5R)-5-Phenyl-pyrrolidine-2-acetic acid;
H-.beta.3-H5PhePyrr2-OH (2S, 5S)-5-Phenyl-pyrrolidine-2-acetic acid;
H-.beta.3-H4Hyp1-OH (2S, 4S)-4-Hydroxy-pyrrolidine-2-acetic acid;
H-.beta.3-H4Hyp2-OH (2S, 4R)-4-Hydroxy-pyrrolidine-2-acetic acid;
H-.beta.3-H4Mp1-OH (2R, 4S)-4-Mercapto-pyrrolidine-2-acetic acid;
H-.beta.3-H4Mp2-OH (2R, 4R)-4-Mercapto-pyrrolidine-2-acetic acid;
H-.beta.3-HPip-OH (2S)-Piperidine-2-acetic acid;
H-.beta.3-HPro-OH (2S)-Pyrrolidine-2-acetic acid;
Ahb 4-Amino-2-hydroxy butyric acid;
H-.gamma.4-DiHCit-OH (4S)-4-Amino-7-carbamidyl-heptanoic acid;
H-.gamma.4-DiHOrn-OH (4S)-4,7-Diamino-heptanoic acid;
H-.gamma.4-DiHtBuA-OH (4R)-4-Amino-6,6-dimethyl-heptanoic acid;
H-.gamma.4-DiHSar-OH N-Methyl-4-amino-butyric acid;
H-.gamma.4-DiHPen-OH (4R)-4-Amino-5-methyl-5-mercapto-hexanoic acid;
H-.gamma.4-DiHtBuG-OH (4R)-4-Amino-5,5-dimethyl-hexanoic acid;
H-.gamma.4-DiH4AmPhe-OH (4R)-4-Amino-5-(4'-aminophenyl)-pentanoic acid;
H-.gamma.4-DiH3AmPhe-OH (4R)-4-Amino-5-(3'-aminophenyl)-pentanoic acid;
H-.gamma.4-DiH2AmPhe-OH (4R)-4-Amino-5-(2'-aminophenyl)-pentanoic acid;
H-.gamma.4-DiHPhe(mC(NH2)=NH)-OH (4R)-4-Amino-5-(3'-amidinophenyl)-pentanoic acid;
H-.gamma.4-DiHPhe(pC(NH2)=NH)-(4R)-4-Amino-5-(4'-amidinophenyl)-pentanoic acid;
OH
H-.gamma.4- (4R)-4-Amino-5-(3'-guanidino-phenyl)-pentanoic DiHPhe(mNHC(NH2)=NH)-acid;
OH
H-.gamma.4- (4R)-4-Amino-5-(4'-guanidino-phenyl)-pentanoic DiHPhe(pNHC(NH2)=NH)-OH acid;
H-.gamma.4-DiH2Pal-OH (4R)-4-Amino-5-(pyridine-4'-yl)-pentanoic acid;

or a respective stereoisomer or N-methyl derivative.

7. A compound according to any of claims 1 to 6 selected from:
benzyl N-[(12R,16S,18S)-16-[(tert-butoxycarbonyl)amino]-8,13-dioxo-20-oxa-9,14-diazatetracyclo[19.3.1.0 2,7.0 14,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-yl]carbamate;
tert-butyl N-[(12R,16S,18S)-12-amino-8,13-dioxo-20-oxa-9,14-diazatetracyclo[19.3.1.0 2,7.0 14,18]pentacosa-1(25),2,4,6,21,23-hexaen-16-yl]carbamate;
benzyl N-[(12R,16S,18S)-16-amino-8,13-dioxo-20-oxa-9,14-diazatetracyclo[19.3.1.0 2,7.0 14,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-yl]carbamate;
tert-butyl N-[(12R,16S,18S)-12-{[2-(1-naphthyl)acetyl]amino)-8,13-dioxo-20-oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18]pentacosa-1(25),2,4,6,21,23-hexaen-16-yl]carbamate;
N-[(12R,16S,18S)-16-amino-8,13-dioxo-20-oxa-9,14-diazatetracyclo[19.3.1.0 2,7.0 14,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-yl]-2-(1-naphthyl)acetamide;
methyl N-[(12R,16S,18S)-12-{[2-(1-naphthyl)acetyl]amino}-8,13-dioxo-20-oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18]pentacosa-1(25),2,4,6,21,23-hexaen-16-yl]carbamate;
N-[(12R,16S,18S)-8,13-dioxo-16-{[2-(1-pyrrolidinyl)acetyl]amino)-20-oxa-9,14-diazatetracyclo[1 9.3.1.0 2,7 .0 14,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-yl]-2-(1-naphthyl)acetamide;
N-[(12R,16S,18S)-16-(dimethylamino)-8,13-dioxo-20-oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-yI]-2-(1-naphthyl)acetamide;

(12 R,16S,18S)-12,16-diamino-20-oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18]pentacosa-1(25),2,4,6,21,23-hexaene-8,13-dione;
benzyl N-[(12R,16S,185)-16-{[2-(2-naphthyl)acetyl]amino}-8,13-dioxo-20-oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-yl]carbamate;
N-[(12R,16S,18S)-12-amino-8,13-dioxo-20-oxa-9,14-diazatetracyclo[1 9.3.1.0 2,7 .0 14,18]pentacosa-1(25),2,4,6,21,23-hexaen-16-yl]-2-(2-naphthyl)acetamide;
2-(dimethylamino)-N-[(12R,16S,18S)-16-{[2-(2-naphthyl)acetyl]amino}-8,13-dioxo-oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-yl]acetamide;
3-methyl-N-[(12R,16S,18S)-16-{[2-(2-naphthyl)acetyl]amino}-8,13-dioxo-20-oxa-9,14-diazatetracyclo[1 9.3.1.0 2,7 .0 14,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-yl]butanamide;
benzyl N-[(12R,16S,18S)-8,13-dioxo-16-[(phenoxycarbonyl)amino]-20-oxa-9,14-diazatetracyclo[19.3.1.0 2,7 .0 14,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-yl]carbamate;
benzyl N-[(10S,12S,16S)-12-[(tert-butoxycarbonyl)amino]-20-methyl-15,21-dioxo-

8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14]hexacosa-1(26),2,4,6,22,24-hexaen-16-yl]carbamate;
tert-butyl N-[(10S,12S,16S)-16-amino-20-methyl-15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14]hexacosa-1(26),2,4,6,22,24-hexaen-12-yl]carbamate;
benzyl N-[(10S,12S,16S)-12-amino-20-methyl-15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14]hexacosa-1(26),2,4,6,22,24-hexaen-16-yl]carbamate;
benzyl N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino}-15,21-dioxo-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14]hexacosa-1(26),2,4,6,22,24-hexaen-16-yl]carbamate;
N-[(10S,12S,168)-16-amino-20-methyl-15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14]hexacosa-1(26),2,4,6,22,24-hexaen-12-yl]-2-(2-naphthyl)acetamide;
2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino)-15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14]hexacosa-1(26),2,4,6,22,24-hexaen-16-yl]acetamide;
N-[(10S,12S,16S)-16-[(cyclopropylsulfonyl)amino]-20-methyl-15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7 .0 10,14]hexacosa-1(26),2,4,6,22,24-hexaen-12-yl]-2-(2-naphthyl)acetamide;

N-[(10S,12S,16S)-20-methyl-16-{[(methylamino)carbonyl]amino}-15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7.0 10,14]hexacosa-1(26),2,4,6,22,24-hexaen-12-yl]-2-(2-naphthyl)acetamide;
2-methoxy-N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthy)acetyl]amino}-15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7.0 10,14]hexacosa-1(26),2,4,6,22,24-hexaen-16-yl]acetamide;
3-methyl-N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino)-15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7.0 10,14]hexacosa-1(26),2,4,6,22,24-hexaen-16-yl]butanamide;
N-[(10S,12S,16S)-20-methyl-15,21-dioxo-16-[(2-phenylacetyl)amino]-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7.0 10,14]hexacosa-1(26),2,4,6,22,24-hexaen-12-yl]-2-(2-naphthyl)acetamide;
N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino}-15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7.0 10,14]hexacosa-1(26),2,4,6,22,24-hexaen-yl]benzamide;
N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino)-15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7.0 10,14]hexacosa-1(26),2,4,6,22,24-hexaen-yl]butanamide;
N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino}-15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7.0 10,14]hexacosa-1(26),2,4,6,22,24-hexaen-yl]pentanamide;
2-{[(10S,12S,16S)-16-{[2-(dimethylamino)acetyl]amino}-20-methyl-15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.02.7.0 10,14]hexacosa-1(26),2,4,6,22,24-hexaen-12-yl]amino}acetic acid;
2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-12-{[(methylamino)carbothioyl]amino}-15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7.0 10,14]hexacosa-1(26),2,4,6,22,24-hexaen-16-yl]acetamide;
2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-15,21-dioxo-12-[(2-sulfanylacetyl)amino]-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7.0 10,14]hexacosa-1(26),2,4,6,22,24-hexaen-16-yl]acetamide;
2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-15,21-dioxo-12-{[2-(tritylsulfanyl)acetyl]amino}-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7.0 10,14]hexacosa-1(26),2,4,6,22,24-hexaen-16-yl]acetamide;

2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-12-{[(methylamino)carbonyl]amino)-15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7.0 10,14]hexacosa-1(26),2,4,6,22,24-hexaen-16-yl]acetamide;
2-(dimethylamino)-N-[(10S,12S,16S)-12-({[3-(dimethylamino)anilino]carbonyl}amino)-20-methyl-15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7.0 10,14]hexacosa-1(26),2,4,6,22,24-hexaen-16-yl]acetamide;
2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-12-{[(2-naphthylamino)carbonyl]amino)-15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7.0 10,14]hexacosa-1(26),2,4,6,22,24-hexaen-16-yl]acetamide;
2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-12-[(methylsulfonyl)amino]-15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7.0 10,14]hexacosa-1(26),2,4,6,22,24-hexaen-16-yl]acetamide;
N-[(10S,12S,16S)-12-[(benzylsulfonyl)amino]-20-methyl-15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7.0 10,14]hexacosa-1(26),2,4,6,22,24-hexaen-16-yl]-(dimethylamino)acetamide;
tert-butyl N-[(10S,12S,16S)-16-{[2-(dimethylamino)acetyl]amino)-20-methyl-15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7.0 10,14]hexacosa-1(26),2,4,6,22,24-hexaen-12-yl]carbamate;
N-[(10S,12S,16S)-12-amino-20-methyl-15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7.0 10,14]hexacosa-1(26),2,4,6,22,24-hexaen-16-yl]-(dimethylamino)acetamide;
ethyl 2-{[(10S,12S,16S)-16-{[2-(dimethylamino)acetyl]amino}-20-methyl-15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7.0 10,14]hexacosa-1(26),2,4,6,22,24-hexaen-12-yl]amino}acetate;
benzyl (10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7]docosa-1(22),2,4,6,18,20-hexaene-15-carboxylate;
(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7]docosa-1(22),2,4,6,18,20-hexaene-15-carboxylic acid;
(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16-diazatricyclo[16.3.1.0 21docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide;
(10R,15S)-4-methoxy-N,10,16-trimethyl-12,17-dioxo-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7]docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide;
(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-N-phenyl-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7]docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide;

(10R,15S)-4-methoxy-10,16-dimethyl-15-(1-pyrrolidinylcarbonyl)-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7]docosa-1(22),2,4,6,18,20-hexaene-12,17-dione;
(10R,15S)-N-[2-(dimethylamino)ethyl]-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7]docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide;
tert-butyl N-[3-({[(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7]docosa-1(22),2,4,6,18,20-hexaen-15-yl]carbonyl}amino)propyl]carbamate;
(10R,15S)-N-(3-aminopropyl)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7]docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide;
(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-N-(3-pyridinylmethyl)-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7]docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide;
(10R,15S)-4-methoxy-N-(2-methoxyethyl)-10,16-dimethyl-12,17-dioxo-8-oxa-11 ,16-diazatricyclo[1 6.3.1.0 2,7]docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide;
(10R,15S)-N-cyclopropyl-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7]docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide;
(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-N-(2,2,2-trifluoroethyl)-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7]docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide (10R,15S)-N-isobutyl-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7]docosa-1(22),2,4 ,6,18,20-hexaene-15-carboxamide;
(10R,15S)-N-(2-hydroxyethyl)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7]docosa-1(22),2,4 ,6,18,20-hexaene-15-carboxamide;
tert-butyl 2-({[(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7]docosa-1(22),2,4,6,18,20-hexaen-15-yl]carbonyl}amino)acetate;
2-({ [(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7]docosa-1(22),2,4,6,18,20-hexaen-15-yl]carbonyl}amino)acetic acid;
(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-N-[(1S)-1-phenylethyl]-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7]docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide;
(10R,15S)-N-[2-(dimethylamino)ethyl]-4-methoxy-N,10,16-trimethyl-12,17-dioxo-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7]docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide;
(10R,15S)-4-methoxy-10,16-dimethyl-N-(1-naphthylmethyl)-12,17-dioxo-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7]docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide;

(10R,15S)-4-methoxy-10,16-dimethyl-N-(2-naphthylmethyl)-12,17-dioxo-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7]docosa-1(22),2,4,6,18,20-hexaene-15-carboxamide;
(10 R,15S)-15-(hydroxymethyl)-4-methoxy-10,16-dimethyl-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7]docosa-1(22),2,4 ,6,18,20-hexaene-12 ,17-dione;
(10 R,15S)-4-methoxy-10,16-dimethyl-15-[(3-pyridinyloxy)methyl]-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7]docosa-1(22),2,4,6,18,20-hexaene-12,17-dione;
(10R,15S)-15-(azidomethyl)-4-methoxy-10,16-dimethyl-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7]docosa-1(22),2,4,6,18,20-hexaene-12,17-dione;
(10R,15S)-15-(aminomethyl)-4-methoxy-10,16-dimethyl-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7]docosa-1(22),2,4,6,18,20-hexaene-12,17-dione;
N-{[(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7]docosa-1(22),2,4,6,18,20-hexaen-15-yl]methyl)-2-phenylacetamide;
[(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7]docosa-1(22),2,4,6,18,20-hexaen-15-yl]methyl N-phenylcarbamate;
benzyl (9S,14S)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6]docosa-1(21),2(22),3 ,5,17,19-hexaene-14-carboxylate;
(9S,14S)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxylic acid;
(9S,14S)-N,9,15-trimethyl-11,16-dioxo-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6]
docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide;
(9S,14S)-9,15-dimethyl-11 ,16-dioxo-7-oxa-10 ,15-diazatricyclo[15 .3.1.1 2,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide;
(9S,14S)-9,15-dimethyl-11,16-dioxo-N-phenyl-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide;
(9S,14S)-9,15-dimethyl-11,16-dioxo-N-phenethyl-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide;
(9S,14S)-9,15-dimethyl-N-(1-naphthylmethyl)-11,16-dioxo-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide;
(9S,14S)-9,15-dimethyl-11,16-dioxo-N-(3-pyridinyl methyl)-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide;
(9S,14S)-9,15-dimethyl-11,16-dioxo-N-[(1S)-1-phenylethyl]-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide;

(9S,14S)-N-(2-methoxyethyl)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide;
(9S,14S)-9,15-dimethyl-11,16-dioxo-N-(2 ,2,2-trifluoroethyl)-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide;
(9S,14S)-N-cyclopropyl-9,15-dimethyl-11,16-dioxo-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide;
(9S,14S)-N-isobutyl-9,15-dimethyl-11,16-dioxo-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6]docosa-1(21),2(22),3 ,5,17,19-hexaene-14-carboxamide;
(9S,14S)-N-(2-hydroxyethyl)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide;
tert-butyl 2-({[(9S,14S)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6]docosa-1(21),2(22),3,5,17,19-hexaen-14-yl]carbonyl}amino)acetate;
2-({[(9S,14S)-9,15-dimethyl-11,16-dioxo-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6]docos 1(21),2(22),3,5,17,19-hexaen-14-yl]carbonyl}amino)acetic acid;
(9S,14S)-N-[2-(dimethylamino)ethyl]-9,15-dimethyl-11,16-dioxo-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide;
(9S,14S)-9,15-dimethyl-11,16-dioxo-N-[3-(1-pyrrolidinyl)propyl]-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide;
(9S,14S)-14-(1-azetanylcarbonyl)-9,15-dimethyl-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6]docosa-1(21),2(22),3,5,17,19-hexaene-11,16-dione;
(9S,14S)-9,15-dimethyl-14-(morpholinocarbonyl)-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6]docosa-1(21),2(22),3,5,17,19-hexaene-11,16-dione;
(9S,14S)-9,15-dimethyl-N-[(1-methyl-1H-imidazol-4-yl)methyl]-11,16-dioxo-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide;
(9S,14S)-9,15-dimethyl-N-(2-naphthylmethyl)-11,16-dioxo-7-oxa-10,15-diazatricyclo[15.3.1.1 2,6]docosa-1(21),2(22),3,5,17,19-hexaene-14-carboxamide;
benzyl (9S,11R)-11-[(tert-butoxycarbonyl)amino]-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaene-carboxylate;
tert-butyl N-[(9S,11R)-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6 .0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-yl]carbamate;

benzyl (9S,11R)-11-amino-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaene-carboxylate;
(9S,11R)-11-amino-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6.0

9,13]hexacosa-1(25),2(26),3,5,21,23-hexaene-14,20-dione;
tert-butyl N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-yl]carbamate;
(9S,11R)-11-amino-16-methyl-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaene-14,20-dione;
N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(2-naphthyl)acetamide;
tert-butyl N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-yl]carbamate;
(9S,11R)-11-amino-16-(3-fluorobenzyl)-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaene-14,20-dione;
N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-yl]acetamide;
N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-yl]acetamide;
N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(1-naphthyl)acetamide;
N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-N'-phenylurea;

N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.12 6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]benzenesulfonamide;
tert-butyl N-[(9S,11R)-1 6-[2-(dimethylamino)acetyl]-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-yl]carbamate;
(9S,11R)-11-amino-16-[2-(dimethylamino)acetyl]-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 26.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaene-14,20-dione;
N-[(9S,11R)-16-[2-(dimethylamino)acetyl]-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.12,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-2-phenylacetamide;
N-[(9S,11R)-16-[2-(dimethylamino)acetyl]-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.12,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]cyclopropanesulfonamide;
N-[(9S,11R)-16-[2-(dimethylamino)acetyl]-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2 6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-N'-methylurea;
tert-butyl N-[(9S,11R)-16-(cyclopropylsulfonyl)-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.12,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]carbamate;
(9S,11R)-11-amino-16-(cyclopropylsulfonyl)-7-oxa-13,16,19,23-tetraazatetracyclo[ 9.3.1.12,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaene-14,20-dione;
N-[(9S,11R)-1 6-(cyclopropylsulfonyl)-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.125.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]benzamide;
tert-butyl N-[(9S,11R)-16-[(methylamino)carbonyl]-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.12,6.09,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]carbamate;
(9S,11R)-11-amino-N-methyl-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaene-carboxamide;

(9S,11R)-11-[(3-fluorobenzoyl)amino]-N-methyl-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[1 9.3.1.1 2,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaene-carboxamide;
allyl N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate;
(13S,16R)-13-amino-16-methyl-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-14-one;
N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-2-(1-naphthyl)acetamide;
N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-2-(2-naphthyl)acetamide;
N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-2-(1-pyrrolidinyl)acetamide;
N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]nicotinamide;
3-methyl-N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]butanamide;
methyl N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate;
N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]cyclopropanesulfonamide;
N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]benzenesulfonamide;
N-methyl-N'-[(13 S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]urea;
N-[(13S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-N'-(3-pyridinyl)urea;
(13S,16R)-13-(isobutylamino)-16-methyl-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-14-one;
(13S,16R)-13-(isopentylamino)-16-methyl-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-14-one;
allyl N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8.lambda.6-thia-15-azatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate;

(13S,16R)-13-amino-16-methyl-18-oxa-8.lambda.6-thia-15-azatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaene-8,8,14-trione;
N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8.lambda.6-thia-15-azatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-2-(1-naphthyl)acetamide;
N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8.lambda.6-thia-15-azatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-2-(2-naphthyl)acetamide;
N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8.lambda.6-thia-15-azatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-2-(1-pyrrolidinyl)acetamide;
N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8.lambda.6-thia-15-azatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]nicotinamide;
3-methyl-N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8.lambda.6-thia-15-azatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]butanamide;
methyl N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8.lambda.6-thia-15-azatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate;
N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8.lambda.6-thia-15-azatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]cyclopropanesulfonamide;
N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8.lambda.6-thia-15-azatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]benzenesulfonamide;
N-methyl-N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8.lambda.6-thia-15-azatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]urea;
N-[(13S,16R)-16-methyl-8,8,14-trioxo-18-oxa-8.lambda.6-thia-15-azatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-N-(3-pyridinyl)urea;
(13S,16R)-13-(isobutylamino)-16-methyl-18-oxa-8.lambda.6-thia-15-azatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaene-8,8,14-trione;
(13S,16R)-13-(isopentylamino)-16-methyl-18-oxa-8.lambda.6-thia-15-azatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaene-8,8,14-trione;
allyl N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate;
(10R,13S)-13-amino-10-methyl-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-12-one;

(10R,13S)-13-(dimethylamino)-10-methyl-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-12-one;
(10R,13S)-13-(isobutylamino)-10-methyl-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-12-one;
(10R,13S)-13-[(3-fluorobenzyl)amino]-10-methyl-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-12-one;
N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]acetamide;
2-methoxy-N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]acetamide;
2-(dimethylamino)-N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]acetamide;
N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]nicotinamide;
3-methyl-N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]butanamide;
tert-butyl N-(3-{[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]amino}-3-oxopropyl)carbamate;
3-amino-N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]propanamide;

N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-2-(1-naphthyl)acetamide;
N-[(10R,13S)-10-methyl-12-oxo-8-oxa-1 8-thia-11,21-diazatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-2-(2-naphthyl)acetamide;
3,3,3-trifluoro-N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]propanamide;

3-fluoro-N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]benzamide;
N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-N-(3-pyridinyl)urea N-methyl-N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl)urea;

tert-butyl 3-[({[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]amino}carbonyl)amino]propanoate;
3-[({[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]amino}carbonyl)amino]propanoic acid;
N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]methanesulfonamide;
N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[7.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]cyclopropanesulfonamide;
N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]benzenesulfonamide;
methyl N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate;
2-methoxyethyl N-[(10R,13S)-10-methyl-12-oxo-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate;
allyl N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18.lambda.6-thia-11,21-diazatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate;
(10 R,13S)-13-amino-10-methyl-8-oxa-18.lambda.6-thia-11,21-diazatricyclo[7.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaene-12,18,18-trione;
(10R,13S)-13-(dimethylamino)-10-methyl-8-oxa-18.lambda.6-thia-11,21-diazatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaene-12,18,18-trione;
(10R,13S)-13-(isobutylamino)-10-methyl-8-oxa-18.lambda.6-thia-11,21-diazatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaene-12,18,18-trione;
(10R,13S)-13-[(3-fluorobenzyl)amino]-10-methyl-8-oxa-18.lambda.6-thia-11,21-diazatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaene-12,18,18-trione;
N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18.lambda.6-thia-11,21-diazatricyclo[l 7.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]acetamide;
2-methoxy-N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18.lambda.6-thia-11,21-diazatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]acetamide;
2-(dimethylamino)-N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18.lambda.6-thia-11,21-diazatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]acetamide;
N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18.lambda.6-thia-11,21-diazatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]nicotinamide;

3-methyl-N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18.lambda.6-thia-11,21-diazatricyclo[17.3.1.0 2.7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]butanamide;
tert-butyl N-(3-{[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18.lambda.6-thia-11,21-diazatricyclo[17.3.1.0 2.7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]amino}-3-oxopropyl)carbamate;
3-amino-N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18.lambda.6-thia-11,21-diazatricyclo[17.3.1.0 2.7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]propanamide;

N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18.lambda.6-thia-11,21-diazatricyclo[17.3.1.0 2.7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-2-(1-naphthyl)acetamide;
N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18.lambda.6-thia-11,21-diazatricyclo[17.3.1.02,7] tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-2-(2-naphthyl)acetamide;
3,3,3-trifluoro-N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18.lambda.6-thia-11,21-diazatricyclo[17.3.1.0 2.7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]propanamide;

3-fluoro-N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18.lambda.6-thia-11,21-diazatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]benzamide;
N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18.lambda.6-thia-11,21-diazatricyclo[17.3.1.0 2.7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-N-(3-pyridinyl)urea;
N-methyl-N'0-R1OR,13S)-10-methyl-12,18,18-trioxo-8-oxa-18.lambda.6-thia-11,21-diazatricyclo[17.3.1.021tricosa-1(23),2,4,6,19,21-hexaen-13-yl]urea;
tert-butyl 3-[({[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18.lambda.6-thia-11,21-diazatricyclo[17.3.1.0 2.7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]amino}carbonyl)amino]propanoate;
3-[({[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18.lambda.6-thia-11,21-diazatricyclo[17.3.1.0 2.7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]amino}carbonyl)amino]propanoic acid;
N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18.lambda.6-thia-11,21-diazatricyclo[l 7.3.1.0 2.7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]methanesulfonamide;
N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18.lambda.6-thia-11,21-diazatricyclo[17.3.1.02.7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]cyclopropanesulfonamide;
N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18.lambda.6-thia-11,21-diazatricyclo[17.3.1.02.7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]benzenesulfonamide;

methyl N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18.lambda.6-thia-11,21-diazatricyclo[17.3.1 .0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate;
2-methoxyethyl N-[(10R,13S)-10-methyl-12,18,18-trioxo-8-oxa-18.lambda.6-thia-11,21-diazatricyclo[17.3.1 .0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]carbamate;
(9S,16S,19R)-16-benzyl-19,20-dimethyl-7-oxa-13,17,20,24-tetraazatetracyclo[20.3.1.1 2,6 .0 9,13]heptacosa-1(26),2(27),3,5,22,24-hexaene-14,18,21-trione;
(9S,19S)-19-benzyl-20-methyl-7-oxa-13,17,20,24-tetraazatetracyclo[20.3.1.1 2,6 .0 9,13]heptacosa-1(26),2(27) ,3,5,22,24-hexaene-14,18,21-trione;
(9S,19S)-19-benzyl-7-oxa-13,17,20 ,24-tetraazatetracyclo[20 .3.1.1 2,6 .0 9,13]heptacosa-1(26),2(27),3,5,22,24-hexaene-14,18,21-trione;
(9S,16R,19S)-19-benzyl-16,17,20-trimethyl-7-oxa-13,17,20,24-tetraazatetracyclo[20.3.1.1 2,6 .0 9,13]heptacosa-1(26),2(27),3,5,22,24-hexaene-14,18,21-trione;
(9S,16R)-16,17,20-trimethyl-7-oxa-13,17,20,24-tetraazatetracyclo[20.3.1.1 2,6 .0 9,13]heptacosa-1(26),2(27),3 ,5,22,24-hexaene-14,18,21-trione;
(9S,16R,19S)-19-benzyl-16,17-dimethyl-7-oxa-13,17,20,24-tetraazatetracyclo[20.3.1.1 2,6 .0 9,13]heptacosa-1(26),2(27),3,5,22,24-hexaene-14,18,21-trione;
(9S,16S)-16-benzyl-21-methyl-7-oxa-13,17,21,25-tetraazatetracyclo[21.3.1.1 2,6 .0 9:2]octacosa-1(27),2(28),3 ,5,23,25-hexaene-14,18,22-trione;
3-[(9S,16R,19S)-16,17,20-trimethyl-14,18,21-trioxo-7-oxa-13,17,20,24-tetraazatetracyclo[20.3.1.1 2,6 .0 9,13]heptacosa-1(26),2(27),3,5,22,24-hexaen-yl]propanoic acid;
(9S,16R,22S)-16,17,20,22,23-pentamethyl-7-oxa-13,17,20,23,27-pentaazatetracyclo[23.3.1.1 2,6 .0 9,13]triaconta-1(29),2(30),3,5,25,27-hexaene-14,18,21,24-tetrone;
(9S,16R,22S)-16,17,22-trimethyl-7-oxa-13,17,20,23,27-pentaazatetracyclo[23.3.1.1 2,6 .0 9,13]triaconta-1(29),2(30),3,5,25,27-hexaene-14,18,21,24-tetrone;

(9S,19R,22S)-16,19,20,22,23-pentamethyl-7-oxa-13,16,20,23,27-pentaazatetracyclo[23.3.1.12,6.09,13]triaconta-1(29),2(30),3,5,25,27-hexaene-14,17,21,24-tetrone;
(9S,18S,22R)-16,18,19,22,23-pentamethyl-7-oxa-13,16,19,23,27-pentaazatetracyclo[23.3.1.12,6.09,13]triaconta-1(29),2(30),3,5,25,27-hexaene-14,17,20,24-tetrone;
(9S,18S,21R)-18-benzyl-21,22-dimethyl-7-oxa-13,16,19,22,26-pentaazatetracyclo[22.3.1.12,6.09,13]nonacosa-1(28),2(29),3,5,24,26-hexaene-14,17,20,23-tetrone;
(9S,18S,21R)-18-benzyl-16,21-dimethyl-7-oxa-13,16,19,22,26-pentaazatetracyclo[22.3.1.12,6.09,13]nonacosa-1(28),2(29),3,5,24,26-hexaene-14,17,20,23-tetrone;
(9 S,18S,21 R)-18-benzyl-16,21,22-trimethyl-7-oxa-13,16,19,22,26-pentaazatetracyclo[22.3.1.12,6.09,13]nonacosa-1(28),2(29),3 ,5,24,26-hexaene-14,17,20,23-tetrone;
3-[(9 S,16R,19 S,22S)-16,17,19,23-tetramethyl-14,18,21,24-tetraoxo-7-oxa-13,17,20,23,27-pentaazatetracyclo[23.3.1.12,6.09,13]triaconta-1(29),2(30) ,3, 5,25,27-hexaen-22-yl]propanoic acid;
3-[(9S,15S,18R,21S)-18-benzyl-15,22-dimethyl-14,17,20,23-tetraoxo-7-oxa-13,16,19,22,26-pentaazatetracyclo[22.3.1.12,6.09,13]nonacosa-1(28),2(29),3,5,24,26-hexaen-21-yl]propanoic acid;
3-[(9S,15R,18S,21S)-18-benzyl-15,22-dimethyl-14,17,20,23-tetraoxo-7-oxa-13,16,19,22,26-pentaazatetracyclo[22.3.1.126.09,11nonacosa-1(28),2(29),3,5,24,26-hexaen-21-yl]propanoic acid;
(9S,16R,19S,22R)-19-(4-aminobutyl)-16,17,22-trimethyl-7-oxa-13,17,20,23,27-pentaazatetracyclo[23.3.1.12,6.09,13]triaconta-1(29),2(30),3,5,25,27-hexaene-14,18,21,24-tetrone;
benzyl (10 S,12S)-12-[(tert-butoxycarbonyl)amino]-15,21-dioxo-8-oxa-3,14,17,20-tetraazatetracyclo[20.2.2.0z7.010,14]hexacosa-1(24),2,4,6,22,25-hexaene-17-carboxylate;
benzyl (10S,12S)-12-amino-15,21-dioxo-8-oxa-3,14,17,20-tetraazatetracyclo[20.22.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaene-17-carboxylate;

tert-butyl N-[(10S,12S)-15,21-dioxo-8-oxa-3,14,17,20-tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaen-12-yl]carbamate;
tert-butyl N-[(10S,12S)-17-methyl-15,21-dioxo-8-oxa-3,14,17,20-tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaen-12-yl]carbamate;
(10S,12S)-12-amino-17-methyl-8-oxa-3,14,17,20-tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaene-15,21-dione;
N-[(10S,12S)-17-methyl-15,21-dioxo-8-oxa-3,14,17,20-tetraazatetracyclo[20.2.2.02,7.010.14]hexacosa-1(24),2,4,6,22,25-hexaen-12-yl]-2-(1-naphthyl)acetamide;
3-methyl-N-[(10S,12S)-17-methyl-15,21-dioxo-8-oxa-3,14,17,20-tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaen-12-yl]butanamide;
N-[(10S,12S)-17-methyl-15,21-dioxo-8-oxa-3,14,17,20-tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaen-12-yl]-N'-(3-pyridinyl)urea;
N-[(10S,12S)-17-methyl-15,21-dioxo-8-oxa-3,14,17,20-tetraazatetracyclo[202.2.02,7.0 10,14]hexacosa-1(24),2,4,6,22,25-hexaen-12-yl]benzenesulfonamide;
tert-butyl N-[(10S,12S)-1742-(dimethylamino)acetyl]-15,21-dioxo-8-oxa-3,14,17,20-tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaen-12-yl]carbamate;
(10S,125)-12-amino-1742-(dimethylamino)acetyl]-8-oxa-3,14,17,20-tetraazatetracyclo[20.2.2.0z7.010,11hexacosa-1(24),2,4,6,22,25-hexaene-15,21-dione;
N-[(10S,12S)-1742-(dimethylamino)acetyl]-15,21-dioxo-8-oxa-3,14,17,20-tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaen-12-yl]-phenylacetamide;
N-[(10S,12S)-17-[2-(dimethylamino)acetyl]-15,21-dioxo-8-oxa-3,14,17,20-tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaen-12-yl]-/V-methylurea;
N-[(10S,12S)-1742-(dimethylamino)acetyl]-15,21-dioxo-8-oxa-3,14,17,20-tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaen-12-yl]cyclopropanesulfonamide;

benzyl (10S,12S)-12-(acetylamino)-15,21-dioxo-8-oxa-3,14,17,20-tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaene-17-carboxylate;
N-[(10S,12S)-15,21-dioxo-8-oxa-3,14,17,20-tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaen-12-yl]acetamide;
N-[(10S,12S)-17-(3-fluorobenzyl)-15,21-dioxo-8-oxa-3,14,17,20-tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaen-12-yl]acetamide;
N-[(10S,12S)-15,21-dioxo-17-[2-(1-pyrrolidinyl)acetyl]-8-oxa-3,14,17,20-tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaen-12-yllacetamide;
(10S,12S)-12-(acetylamino)-15,21-dioxo-N-phenyl-8-oxa-3,14,17,20-tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaene-17-carboxamide;
N-[(10S,12S)-15,21-dioxo-17-(phenylsulfonyl)-8-oxa-3,14,17,20-tetraazatetracyclo[20.2.2.02,7.010,14Thexacosa-1(24),2,4,6,22,25-hexaen-12-yl]acetamide;
3-({[(10S,128)-12-(acetylamino)-15,21-dioxo-8-oxa-3,14,17,20-tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaen-17-yl]carbonyllamino)propanoic acid;
tert-butyl 3-({[(10S,12S)-12-(acetylamino)-15,21-dioxo-8-oxa-3,14,17,20-tetraazatetracyclo[20.2.2.02,7.010,14]hexacosa-1(24),2,4,6,22,25-hexaen-17-yl]carbonyllamino)propanoate;
methyl (85,17S,195)-17-[(tert-butoxycarbonyl)amino]-24-fluoro-6,14-dioxo-10,21-dioxa-4-thia-7,15-diazatetracyclo[20.3.1.12,5.015,19]heptacosa-1(26),2,5(27),12,22,24-hexaene-8-carboxylate;
methyl (8S,17S,19S)-17-[(tert-butoxycarbonyl)amino]-24-fluoro-6,14-dioxo-10,21-dioxa-4-thia-7,15-diazatetracyclo[20.3.1.12,5.015,19]heptacosa-1(26),2,5(27),22,24-pentaene-8-carboxylate;
methyl (8S,175,19S)-17-amino-24-fluoro-6,14-dioxo-10,21-dioxa-4-thia-7,15-diazatetracyclo[20.3.1.12,5.015,19]heptacosa-1(26),2,5(27),22,24-pentaene-8-carboxylate;

methyl (8S,17S,19S)-24-fluoro-6,14-dioxo-17-[(2-phenylacetyl)amino]-10,21-dioxa-4-thia-7,15-diazatetracyclo[20.3.1.125.015,19]heptacosa-1(26),2,5(27),22,24-pentaene-8-carboxylate;
(8S,17S,19S)-24-fluoro-6,14-dioxo-17-[(2-phenylacetyl)amino]-10,21-dioxa-4-thia-7,15-diazatetracyclo[20.3.1.12,5.015,19]heptacosa-1(26),2,5(27),22,24-pentaene-carboxylic acid;
(8S,17S,19S)-24-fluoro-6,14-dioxo-17-[(2-phenylacetyl)amino]-10,21-dioxa-4-thia-7,15-diazatetracyclo[20.3.1.12,5.015,19]heptacosa-1(26),2,5(27),22,24-pentaene-carboxamide;
(8S,17S,19S)-24-fluoro-N-isobutyl-6,14-dioxo-17-[(2-phenylacetyl)amino]-10,21-dioxa-4-thia-7,15-diazatetracyclo[20.3.1.12,5.015,19]heptacosa-1(26),2,5(27),22,24-pentaene-8-carboxamide;
methyl (8S,12E,18S,20S)-18-[(tert-butoxycarbonyl)amino]-25-fluoro-6,15-dioxo-

10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.125.016,29]octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxylate;
(8S,12E,18S,20S)-18-[(tert-butoxycarbonyl)amino]-25-fluoro-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.125.016,20]octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxylic acid;
methyl (8S,12E, 18S,20S)-18-amino-25-fluoro-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.12,5.016,20]octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxylate;
methyl (8S,12E, 18S,20S)-25-fluoro-18-[2-(2-naphthyl)acetyl]amino-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.12,5.016,20]octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxylate;
tert-butyl N-[(8S,12E, 18S,20S)-25-fluoro-8-[(isobutylamino)carbonyl]-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.125.01620]octacosa-1(27),2,5(28),12,23,25-hexaen-18-yl]carbamate;
(8S,12E,18S,20S)-18-amino-25-fluoro-N-isobutyl-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.12,5.016,20]octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxamide;
(8S,12E,18S,20S)-25-fluoro-N-isobutyl-6,15-dioxo-18-[(3-pyridinylcarbonyl)amino]
10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.125.016,20]octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxamide;

tert-butyl N-R8S,12E,18S,20S)-8-(anilinocarbonyl)-25-fluoro-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5.0 16,20]octacosa-1(27),2,5(28),12,23,25-hexaen-18-yl]carbamate;
(8S,12E,18S,20S)-18-amino-25-fluoro-6,15-dioxo-N-phenyl-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5.0 16,20]octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxamide;
methyl (8S,12E,18S,20S)-25-fluoro-6,15-dioxo-18-[(2-phenylacetypamino]-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5.0 16,20octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxylate;
(8S,12E,18S,20S)-25-fluoro-6,15-dioxo-18-[(2-phenylacetyl)amino]-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5.0 16,20]octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxylic acid;
methyl (8S,12E,18S,20S)-18-[(3-chlorobenzoyl)amino]-25-fluoro-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 25.0 16,20]octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxylate;
(8S,12E,18S,20S)-18-[(3-chlorobenzoyl)amino]-25-fluoro-6,15-dioxo-10,22-dioxa-thia-7,16-diazatetracyclo[21.3.1.1 2,5.0 16,20]octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxylic acid;
(8S,12E,18S,20S)-25-fluoro-N-isobutyl-18-{[2-(2-naphthyl)acetyl]amino}-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5.0 16,20]octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxamide;
(8S,12E,18S,20S)-25-fluoro-18-{[2-(2-naphthyl)acetyl]amino)-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5.0 16,20]octacosa-1(27),2,5(28),12,23,25-hexaene-8-carboxylic acid;
methyl (8S,18S,20S)-18-[(tert-butoxycarbonyl)amino]-25-fluoro-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5.0 16,20]octacosa-1(27),2,5(28),23,25-pentaene-8-carboxylate;
(8S,18S,20S)-18-[(tert-butoxycarbonyl)amino]-25-fluoro-6,15-dioxo-10,22-dioxa-thia-7,16-diazatetracyclo[21.3.1.1 25.0 16,20]octacosa-1(27),2,5(28),23,25-pentaene-8-carboxylic acid;
methyl (8S,18S,20S)-18-amino-25-fluoro-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5.0 16,21octacosa-1(27),2,5(28),23,25-pentaene-8-carboxylate;

methyl (8S,18S,20S)-25-fluoro-18-{[2-(2-naphthyl)acetyl]amino)-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21 .3.1 .12,5.016,2c]octacosa-1(27),2,5(28),23,25-pentaene-8-carboxylate;
tert-butyl N-R8S,18S,20S)-8-(anilinocarbonyl)-25-fluoro-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.12,5.0 16,20]octacosa-1(27),2,5(28),23,25-pentaen-yl]carbamate;
(8S,18S,20S)-18-amino-25-fluoro-6,15-dioxo-N-phenyl-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.12,5.0 16,20]octacosa-1(27),2,5(28),23,25-pentaene-8-carboxamide;
methyl (8S,18S,20S)-25-fluoro-6,15-dioxo-18-[(2-phenylacetyl)amino]-10,22-dioxa-thia-7,16-diazatetracyclo[21.3.1.12,5.016,20]octacosa-1(27),2,5(28),23,25-pentaene-8-carboxylate;
(8S,18S,20S)-18-[(3-chlorobenzoyl)amino]-25-fluoro-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.12,5.016,20]octacosa-1(27),2,5(28),23,25-pentaene-carboxylic acid;
methyl (8S,18S,20S)-18-[(3-chlorobenzoyl)amino]-25-fluoro-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.125.016,20]octacosa-1(27),2,5(28),23,25-pentaene-8-carboxylate;
(8S,18S,20S)-25-fluoro-6,15-dioxo-18-[(2-phenylacetypamino]-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.125.016,20]octacosa-1 (27),2,5(28),23,25-pentaene-carboxylic acid;
(8S,18S,20S)-25-fluoro-18-{[2-(2-naphthypacetyl]amino}-6,15-dioxo-10,22-dioxa-thia-7,16-diazatetracyclo[21.3.1.12,5.016,20]octacosa-1(27),2,5(28),23,25-pentaene-8-carboxylic acid;
tert-butyl N-[(8S,18S,20S)-25-fluoro-8-[(isobutylamino)carbonyl]-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.12,5.0 16,20]octacosa-1 (27),2,5(28),23,25-pentaen-18-yl]carbamate;
(8S,18S,20S)-18-amino-25-fluoro-N-isobutyl-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.125.016,20]octacosa-1(27),2,5(28),23,25-pentaene-8-carboxamide;
(8S,18S,20S)-25-fluoro-N-isobutyl-6,15-dioxo-18-[(3-pyridinylcarbonyl)amino]-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.125.0 16,20]octacosa-1(27),2,5(28),23,25-pentaene-8-carboxamide;

tert-butyl N-R8S,18S,20S)-8-[(4-chloroanilino)carbonyl]-25-fluoro-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo{21.3.1.12,5.016,20]octacosa-1(27),2,5(28),23,25-pentaen-18-yl]carbamate;
(8S,18S,20S)-18-amino-N-(4-chlorophenyl)-25-fluoro-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.12,5.016,20]octacosa-1(27),2,5(28),23,25-pentaene-carboxamide;
tert-butyl N-[(8S,18S,20S)-25-fluoro-6,15-dioxo-8-(3-toluidinocarbonyl)-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.125.016,20]octacosa-1(27),2,5(28),23,25-pentaen-18-yl]carbamate;
(8S,18S,20S)-18-amino-25-fluoro-N-(3-methylphenyl)-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.125.016.20]octacosa-1(27),2,5(28),23,25-pentaene-8-carboxamide;
tert-butyl N-[(8S,18S,20S)-8-[(benzylamino)carbonyl]-25-fluoro-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.12,5.016,20]octacosa-1(27),2,5(28),23,25-pentaen-18-yl]carbamate;
(80S,18S,20S)-18-amino-N-benzyl-25-fluoro-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.12,5.016,20]octacosa-1(27),2,5(28),23 ,25-pentaene-8-carboxamide;
benzyl N-[(9S,11S,15S)-11-[(4-bromobenzyl)oxy]-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[1 8.2.1.026.09,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-yl]carbamate;
(9S,11S,15S)-15-amino-11-hydroxy-18,21-dimethyl-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraene-14,19-dione;
(9S,11S,15S)-15-amino-11-(benzyloxy)-18,21-dimethyl-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraene-14,19-dione;
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-yl]-2-(2-naphthyl)acetamide;
N-[(9S,11S,15S)-11-(benzyloxy)-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-yl]acetamide;
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.02,6.09,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-yl]-2-(1-naphthyl)acetamide;

N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6.0 9,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-yl]-3-methylbutanamide;
3-fluoro-N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6.0 9,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-yl]benzamide;
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6.0 9,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-yl]benzenesulfonamide;
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6.0 9,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-yl]methanesulfonamide;
methyl N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6.0 9,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-yl]carbamate;
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6.0 9,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-yl]-N'-methylurea;
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6.0 9,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-yl]-N'-(3-pyridinyl)urea;
N-[(9S,11S,15S)-11-methoxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6.0 9,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-yl]-2-(2-naphthyl)acetamide;
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,1 9-dioxo-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6.0 9,13]tricosa-1(22),2(6),4,20 (23)-tetraen-15-yl]-N'-(2-naphthyl)urea;
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6.0 9,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-yl]-2-phenylacetamide;
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6.0 9,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-yl]-3-methoxybenzamide;

N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6.0 9,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-yl]-2-naphthalenesulfonamide;
3-(4-fluorophenyl)-N-R9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6.0 9,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-yl]propanamide;
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6.0 9,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-yl]-2-(1H-indol-3-yl)acetamide;
(9S,11S,15S)-11-hydroxy-18,21-dimethyl-15-{[2-(2-naphthyl)ethyl]amino)-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6.0 9,13]tricosa-1(22),2(6),4,20(23)-tetraene-14,19-dione;
(9S,11S,15S)-15-[(4-fluorobenzyl)amino]-11-hydroxy-18,21-dimethyl-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6.0 9,13]tricosa-1(22),2(6),4,20(23)-tetraene-14,19-dione;
benzyl N-[(13S,19S)-4,8-dimethyl-23-nitro-7,14-dioxo-21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6.0 15,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-yl]carbamate;
benzyl N-[(13R,19S)-4,8-dimethyl-23-nitro-7,14-dioxo-21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6.0 15,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-yl]carbamate;
(13S,19S)-13-amino-4,8-dimethyl-23-nitro-21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6.0 15,19]heptacosa-1(24),2(27),3,5,22,25-hexaene-7,14-dione;
benzyl N-[(13S,19S)-23-amino-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6.0 15,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-yl]carbamate;
benzyl N-[(13S,19S)-23-(acetylamino)-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6.0 15,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-yl]carbamate;
N-[(13S,19S)-13-amino-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6.0 15,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-yl]acetamide;

N-(2-chlorophenyl)-N'-[(13S,19S)-4,8-dimethyl-23-nitro-7,14-dioxo-21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6.0 15,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-yl]urea;
N-[(13S,19S)-23-amino-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6.0 15,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-13-yl]-N'-(2-chlorophenyl)urea;
N-[(13S,19S)-13-{[(2-chloroanilino)carbonyl]amino)-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6.0 15,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-23-yl]methanesulfonamide;
N-[(13S,19S)-4,8-dimethyl-23-nitro-7,14-dioxo-21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6.0 15,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-yl]cyclopropanecarboxamide;
N-[(13S,19S)-23-amino-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6.0 15,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-yl]cyclopropanecarboxamide;
N-[(13S,19S)-4,8-dimethyl-23-[(methylsulfonyl)amino]-7,14-dioxo-21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6.0 15,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-yl]cyclopropanecarboxamide;
N-[(13S,19S)-13-amino-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6.0 15,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-yl]methanesulfonamide;
benzyl N-[(13S,19S)-4,8-dimethyl-23-[(methylsulfonyl)amino]-7,14-dioxo-21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6.0 15,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-13-yl]carbamate;
benzyl N-[(13S,19S)-4,8-dimethyl-7,14-dioxo-23-(2-pyrimidinylamino)-21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6.0 15,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-13-yl]carbamate;
(13S,19S)-13-amino-4,8-dimethyl-23-(2-pyrimidinylamino)-21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6.0 15,19]heptacosa-1(24),2(27),3,5,22,25-hexaene-7,14-dione;
N-[(13S,19S)-13-(dimethylamino)-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6.0 15,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-yl]acetamide;

N-[(13S,19S)-23-(acetylamino)-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6.0 15,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-13-yl]-2-phenylacetamide;
N-[(13S,19S)-13-{[(3-chlorophenyl)sulfonyl]amino)-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 26.0 15,19heptacosa-1(24),2(27),3,5,22,25-hexaen-23-yl]acetamide;
N-[(13S,19S)-13-{[(isobutylamino)carbonyl]aminol-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6.0 15,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-23-yl]acetamide;
N-R13S,19S)-4,8-dimethyl-23-[(methylsulfonyl)amino]-7,14-dioxo-21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6.0 15,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-13-yl]-4-fluorobenzamide;
N-[(13S,19S)-13-[(3-fluorobenzyl)amino]-4,8-dimethyl-7,14-dioxo-21-oxa-3,8,15,27-tetraazatetracyclo[20.2.2.1 2,6.0 15,19]heptacosa-1(24),2(27),3,5,22,25-hexaen-yl]methanesulfonamide;
benzyl N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-dibenzo[i, k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]carbamate;
(15R,16aS)-15-amino-10-methyl-10,11,15,16,16a,17-hexahydro-14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecine-9,12-dione;
(15R,16aS)-15-(dimethylamino)-10-methyl-10,11,15,16,16a,17-hexahydro-14H-dibenzo[i, k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecine-9,12-dione;
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]acetamide;
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-3-methylbutanamide;
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-2-(2-naphthyl)acetamide;
N-(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-2-(1-naphthyl)acetamide;
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-2-(dimethylamino)acetamide;

tert-butyl N-(3-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]amino-3-oxopropyl)carbamate;
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-3-aminopropanamide;
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-3-fluorobenzamide;
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]isonicotinamide;
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-N-methylurea;
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-N-(3-pyridinyl)urea;
2-methoxyethyl N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]carbamate;
tert-butyl 3-[({[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]amino}carbonyl)amino]propanoate;
3-[({[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]amino}carbonyl)amino]propanoic acid;
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]methanesulfonamide;
N-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]benzenesulfonamide;
(15R,16aS)-15-[(3-fluorobenzyl)amino]-10-methyl-10,11,15,16,16a,17-hexahydro-14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecine-9,12-dione;
(15R,16aS)-15-(isobutylamino)-10-methyl-10,11,15,16,16a,17-hexahydro-14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecine-9,12-dione;
N"-[(15R,16aS)-10-methyl-9,12-dioxo-9,10,11,12,15,16,16a,17-octahydro-14H-dibenzo[i,k]pyrrolo[2,1-c][1,4,7]oxadiazacyclododecin-15-yl]-N,N,N,N-tetramethylguanidine;

benzyl (16S,18S)-16-[(tert-butoxycarbonyl)amino]-7,13-dioxo-4-(trifluoromethyl)-5,20-dioxa-3,8,11,14-tetraazatetracyclo[19.3.1.0 2,6.0 14,18]pentacosa-1(25),2(6),3,21,23-pentaene-11-carboxylate;
tert-butyl N-[(16S,18S)-7,13-dioxo-4-(trifluoromethyl)-5,20-dioxa-3,8,11,14-tetraazatetracyclo[19.3.1.0 2,6.0 14,18]pentacosa-1(25),2(6),3,21,23-pentaen-yl]carbamate;
benzyl (16S,18S)-16-amino-7,13-dioxo-4-(trifluoromethyl)-5,20-dioxa-3,8,11,14-tetraazatetracyclo[19.3.1.0 26.0 14,18]pentacosa-1(25),2(6),3,21,23-pentaene-

11-carboxylate;
allyl N-[(12R,16S,18S)-16-[(tert-butoxycarbonyl)amino]-8,13-dioxo-20-oxa-9,14-diazatetracyclo[19.3.1.0 2.7.0 14,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-yl]carbamate;
ally! N-[(12 R,16S,18S)-16-amino-8,13-dioxo-20-oxa-9,14-diazatetracyclop 9.3.1.0 27.0 14,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-yl]carbamate;
2-(1H-imidazol-1-yl)-N-[(12R,16S,18S)-12-{[2-(1-naphthyl)acetyl]amino}-8,13-dioxo-20-oxa-9,14-diazatetracyclo[19.3.1.0 2.7.0 14,18]pentacosa-1(25),2,4,6,21,23-hexaen-16-yl]acetamide;
N-[(12R,16S,18S)-8,13-dioxo-16-{[(3-pyridinylamino)carbonyl]amino}-20-oxa-9,14-diazatetracyclo[19.3.1.0 27.014,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-yI]-2-(1-naphthyl)acetamide;
2-(3-chlorophenyI)-N-[(12R,16S,18S)-8,13-dioxo-16-{[2-(1-pyrrolidinyl)acetyl]amino)-20-oxa-9,14-diazatetracyclo[19.3.1.0 2,7.0 14,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-yllacetamide;
2-cyclohexyl-N-[(12R,16S,18S)-8,13-dioxo-16-{[2-(1-pyrrolidinyl)acetyl]amino}-20-oxa-9,14-diazatetracyclo[19.3.1.0 2.7.0 14,18]pentacosa-1(25),2,4,6,21,23-hexaen-

12-yl]acetamide;
N-[(12R,16S,18S)-12-{[(1-naphthylamino)carbonyl]amino}-8,13-dioxo-20-oxa-9,14-diazatetracyclo[19.3.1.0 27.0 14,18]pentacosa-1(25),2,4,6,21,23-hexaen-16-yl]-2-(1-pyrrolidinyl)acetamide;
N-[(12R,16S,18S)-12-[(benzylsulfonyl)amino]-8,13-dioxo-20-oxa-9,14-diazatetracyclo[19.3.1.0 2,7.0 14,18]pentacosa-1(25),2,4,6,21,23-hexaen-16-yl]-2-(1-pyrrolidinyl)acetamide;
benzyl N-[(12R,16S,18S)-8,13-dioxo-16-{[2-(1-pyrrolidinyl)acetyl]amino}-20-oxa-9,14-diazatetracyclo[19.3.1.0 2,7.0 14,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-yl}carbamate;

N-[(12R,16S,18S)-12-amino-8,13-dioxo-20-oxa-9,14-diazatetracyclo[19.3.1.0 2,7.0 14,18]pentacosa-1(25),2,4,6,21,23-hexaen-16-yl]-2-(1-pyrrolidinyl)acetamide;
N-[(12R,16S,18S)-12-([2-(1-naphthyl)ethyl]amino}-8,13-dioxo-20-oxa-9,14-diazatetracyclo[19.3.1.0 27.0 14,18]pentacosa-1(25),2,4,6,21,23-hexaen-16-yl]-2-(1-pyrrolidinyl)acetamide;
N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(1-naphthyl)acetamide;
N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(2-naphthyl)acetamide;
N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-N-(2-naphthyl)urea;
N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6.0[9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-2-naphthalenesulfonamide;
N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-3-(2-naphthyl)propanamide;
N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-3-phenylpropanamide;
2-(dimethylamino)-N-[(9S,11R)-16-(3-fluorobenzyl)-14,20-dioxo-7-oxa-

13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6.0 9,11hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yflacetamide;
benzyl (9S,11R)-11-{[2-(2-naphthyl)acetyl]amino}-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 26.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaene-carboxylate;
N-[(9S,11R)-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(2-naphthyl)acetamide;

N-[(9S,11R)-16-(3-fluorobenzoyl)-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 25.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(2-naphthyl)acetamide;
N-[(9S,11R)-16-benzyl-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(2-naphthyl)acetamide;
N-[(9S,11R)-14,20-dioxo-16-phenethyl-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 25.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(2-naphthyl)acetamide;
N-[(9S,11R)-14,20-dioxo-16-(3-phenylpropyl)-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 25.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(2-naphthyl)acetamide;
N-[(9S,11R)-16-isopentyl-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo{19.3.1.1 2,6.0 9,13}hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(2-naphthyl)acetamide;
N-[(9S,11R)-16-isobutyl-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(2-naphthylacetamide;
2-(d imethylam ino)ethyl (9 S,11R)-11-{[2-(2-naphthyl)acetyl]ami no}-14 ,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaene-16-carboxylate;
N-[(9S,11R)-16-[2-(dimethylamino)ethyl]-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(2-naphthylacetamide; or 3,3-dimethyl-N-[(9S,11R)-16-methyl-14,20-d ioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-yl]butanamide.
8. A compound according to any of claims 1 to 7 selected from:
tert-butyl N-[(12R,16S,18S)-12-amino-8,13-dioxo-20-oxa-9,14-diazatetracyclo[19.3.1.0 27.0 14,18]pentacosa-1(25),2,4,6,21,23-hexaen-16-yl]carbamate;

N-[(12R,16S,18S)-8,13-dioxo-16-{[2-(1-pyrrolidinyl)acetyl]amino)-20-oxa-9,14-diazatetracyclo[19.3.1.0 27.0 14,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-yl]-2-(1-naphthyl)acetamide;
benzyl N-[(12R,16S,18S)-8,13-dioxo-16-[(phenoxycarbonyl)amino]-20-oxa-9,14-diazatetracyclo[19.3.1.0 2,7.0 14,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-yl]carbamate;
benzyl N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino}-15,21-dioxo-oxa-14,20-diazatetracyclo[20.3.1.0 2,7.0 10,14]hexacosa-1(26),2,4,6,22,24-hexaen-16-yl]carbamate;
2-(dimethylamino)-N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthypacetyl]amino}-15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7.0 10,14]hexacosa-1(26),2,4,6,22,24-hexaen-16-yl]acetamide;
N-[(10S,12S,16S)-16-[(cyclopropylsulfonyl)amino]-20-methyl-15,21-dioxo-8-oxa-

14,20-diazatetracyclo[20.3.1.0 2,7.0 10,14]hexacosa-1(26),2,4,6,22,24-hexaen-12-yl]-2-(2-naphthypacetamide;
3-methyl-N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino}-15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.027.010,14]hexacosa-1(26),2,4,6,22,24-hexaen-16-Abutanamide;
N-[(10S,12S,16S)-20-methyl-15,21-dioxo-16-[(2-phenylacetyl)aminc]-8-oxa-14,20-diazatetracyclo[20.3.1 .027.01014]hexacosa-1(26),2,4,6,22,24-hexaen-12-yl]-2-(2-naphthyl)acetamide;
N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetynamino)-15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.02,7.010,14]hexacosa-1(26),2,4,6,22,24-hexaen-16-yl]benzamide;
N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthyl)acetyl]amino}-15,21-dioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 2,7.0 10,14]hexacosa-1(26),2,4,6,22,24-hexaen-Abutanamide;
N-[(10S,12S,16S)-20-methyl-12-{[2-(2-naphthypacetyl]amino}-15,21-d ioxo-8-oxa-14,20-diazatetracyclo[20.3.1.0 27.0 10,14]hexacosa-1(26),2,4,6,22,24-hexaen-16-yl]pentanamide;
(10R,15S)-4-methoxy-10,16-dimethyl-12,17-dioxo-N-(3-pyridinylmethyl)-8-oxa-11,16-diazatricyclo[16.3.1.0 2,7]docosa-1 (22),2,4,6,18,20-hexaene-15-carboxamide;
tert-butyl N-[(9S,11R)-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-yl]carbamate;

tert-butyl N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-yl]carbamate;
N-[(9S,11R)-1 6-methyl-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(2-naphthyl)acetamide;
N-[(9S,11R)-1 6-(3-fluorobenzyl)-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-yl]acetamide;
N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-11-yl]-2-(1-naphthyl)acetamide;
N-[(9S,11R)-16-methyl-14,20-dioxo-7-oxa-13,16,19,23-tetraazatetracyclo[19.3.1.1 2,6.0 9,13]hexacosa-1(25),2(26),3,5,21,23-hexaen-yl]benzenesulfonamide;
(13 S,16R)-13-amino-16-methyl-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-14-one;
N-[(13 S,16R)-16-methyl-14-oxo-18-oxa-8-thia-15-azatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-13-yl]-2-(1-pyrrolidinyl)acetamide;
(10R,13S)-13-amino-10-methyl-8-oxa-18-thia-11,21-diazatricyclo[17.3.1.0 2,7]tricosa-1(23),2,4,6,19,21-hexaen-12-one;
(8S,18S,20S)-18-amino-25-fluoro-6,15-dioxo-N-phenyl-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5.0 16,20]octacosa-1(27),2,5(28),23,25-pentaene-8-carboxamide;
(8S,18S,20S)-18-amino-N-(4-chlorophenyl)-25-fluoro-6,15-dioxo-10,22-dioxa-4-thia-7,16-diazatetracyclo[21.3.1.1 2,5.0 16,29octacosa-1(27),2,5(28),23,25-pentaene-carboxamide;
(8S,18S,20S)-18-amino-25-fluoro-N-(3-methylphenyl)-6,15-dioxo-10,22-dioxa-4-thia-7,1 6-diazatetracyclo[21.3.1.1 2,5. 0 16,20]octacosa-1 (27),2,5(28),23,25-pentaene-8-carboxamide;
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 26.0 9,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-yl]-2-(2-naphthyl)acetamide;

N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6.0 9,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-yl]-2-(1-naphthyl)acetamide;
N-[(9S,11S,15S)-11-methoxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6.0 9,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-yl]-2-(2-naphthyl)acetamide;
N-[(9S,11S,15S)-11-hydroxy-18,21-dimethyl-14,19-dioxo-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6.0 9,13]tricosa-1(22),2(6),4,20(23)-tetraen-15-yl]-N'-(2-naphthyl)urea;
(9S,11S,15S)-11-hydroxy-18,21-dimethyl-15-{[2-(2-naphthyl)ethyl]amino)-7-oxa-3-thia-13,18,21,22-tetraazatetracyclo[18.2.1.0 2,6.0 9,13]tricosa-1(22),2(6),4,20(23)-tetraene-14,19-dione;
2-(1H-imidazol-1-yl)-N-[(12R,16S,18S)-12-{[2-(1-naphthyl)acetyl]amino)-8,13-dioxo-20-oxa-9,14-diazatetracyclo[19.3.1.0 2,7.0 14,18]pentacosa-1(25),2,4,6,21,23-hexaen-16-yl]acetamide;
N-[(12R,16S,18S)-8,13-dioxo-16-{[(3-pyridinylamino)carbonyl]amino}-20-oxa-9,14-diazatetracyclo[19.3.1.0 2,7.0 14,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-yl]-2-(1-naphthyl)acetamide;
2-(3-chlorophenyl)-N-[(12R,16S,18S)-8,13-dioxo-16-{[2-(1-pyrrolidinyl)acetyl]amino)-20-oxa-9,14-diazatetracyclo[19.3.1.0 2,7.0 14,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-yl]acetamide;
2-cyclohexyl-N-[(12R,16S,18S)-8,13-dioxo-16-{[2-(1-pyrrolidinyl)acetyl]amino}-oxa-9,14-diazatetracyclo[19.3.1.0 2,7.0 14,18]pentacosa-1(25),2,4,6,21,23-hexaen-12-yl]acetamide; or N-[(12R,16S,18S)-12-{[(1-naphthylamino)carbonyl]amino}-8,13-dioxo-20-oxa-9,14-diazatetracyclo[19.3.1.0 2,7.0 14,18]pentacosa-1(25),2,4,6,21,23-hexaen-16-yl]-2-(1-pyrrolidinyl)acetamide.
9. A compound according to any one of claims 1 to 8 for use as a therapeutically active substance.
10. A compound according to claim 9 for use as a therapeutically active substance having i) inhibitory activity on endothelin converting enzyme of subtype 1 (ECE-1), ii) inhibitory activity on the cysteine protease cathepsin S (CatS), iii) antagonistic activity on the oxytocin (OT) receptor), iv) antagonistic activity on the thyrotropin-releasing hormone (TRH) receptor), v) agonistic activity on the bombesin 3 (BB3) receptor, vi) antagonistic activity on the leukotriene B4 (LTB4) receptor, and/or vii) antimicrobial activity against at least one bacterial strain, in particular Staphylococcus aureus or Streptococcus pneumoniae.
11. A pharmaceutical composition comprising a compound or a mixture of compounds according to any one of claims 1 to 8, or pharmaceutically acceptable salt(s) thereof, and at least one therapeutically inert excipient.
12. A pharmaceutical composition according to claim 11 suitable for oral, topical, transdermal, injection, buccal, transmucosal, pulmonary or inhalation administration, particularly in form of tablets, dragees, capsules, solutions, liquids, gels, plaster, creams, ointments, syrup, slurries, suspensions, spray, nebulizer or suppositories.
13. The use of a compound according to any one of claims 1 to 8 for the manufacture of a medicament, having i) inhibitory activity on endothelin converting enzyme of subtype 1 (ECE-1), ii) inhibitory activity on the cysteine protease cathepsin S (CatS), iii) antagonistic activity on the oxytocin (OT) receptor), iv) antagonistic activity on the thyrotropin-releasing hormone (TRH) receptor), v) agonistic activity on the bombesin 3 (BB3) receptor, vi) antagonistic activity on the leukotriene B4 (LTB4) receptor, and/or vii) antimicrobial activity against at least one bacterial strain, in particular Staphylococcus aureus or Streptococcus pneumoniae.
14. The use of a compound according to any one of claims 1 to 8 for the manufacture of a medicament for the prevention or treatment of i) diseases resulting from abnormally high plasma or tissue levels of the potent vasoconstrictive peptide endothelin-1 (ET-1), like systemic and pulmonary hypertension, cerebral vasospasm and stroke, asthma, cardiac and renal failure, atherosclerosis, preeclampsia, benign prostatic hyperplasia, and carcinogenesis; ii) a wide range of diseases related to Cathepsin S, including neuropathic hyperalgesia, obesity, and in particular diseases of the immune system, like rheumatoid arthritis (RA), multiple sclerosis (MS), myasthenia gravis, transplant rejection, diabetes, Sj.SLZERO.grens syndrome, Grave's disease, systemic lupus erythematosis, osteoarthritis, psoriasis, idiopathic thrombocytopenic purpura, allergic rhinitis, asthma, atherosclerosis, and chronic obstructive pulmonary disease (COPD); iii) diseases and conditions associated to an overexpression of oxytocin (OT), like preterm delivery; iv) diseases related to a dysfunction in the homoestatic system of the thyrotropin-releasing hormone (TRH), such as infantile spasms, generalized and refractory partial seizures, edematous and destructive forms of acute pancreatitis, and certain inflammatory disorders (e.g.
autoimmune diseases, inflammatory bowel diseases, cancer-related fatigue or depression, and Alzheimer's disease); v) diseases related to a dysfunction of the bombesin 3 (BB3) receptor, like obesity and impairment of glucose metabolism, disorders of lung development, pulmonary diseases, CNS disorders and carcinogenesis; vi) diseases potentially treatable by blockade of the leukotriene B4 (LTB4) receptor, especially inflammatory and allergic diseases like asthma, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), allergic rhinitis, atopic dermatitis, allergic conjunctivitis, obliterative bronchiolitis after lung transplantation, or interstitial lung diseases;
and/or vii) a wide range of infections caused by microorganisms, in particular strains of Staphylococcus aureus or Streptococcus pneumonia, comprising infections related to: a) respiratory diseases like cystic fibrosis, emphysema, asthma or pneumonia, b) skin or soft tissue diseases such as surgical wounds, traumatic wounds, burn wounds or herpes, smallpox, rubella or measles, c) gastrointestinal diseases including epidemic diarrhea, necrotizing enterocolitis, typhlitis or gastroenteritis or pancreatitis, d) eye diseases such as keratitis and endophthalmitis, e) ear diseases, e.g. otitis, f) CNS
diseases including brain abscess and meningitis or encephalitis, g) bone diseases such as osteochondritis and osteomyelitis, h) cardiovascular diseases like endocartitis and pericarditis, or i) genitourinal diseases such as epididymitis, prostatitis and urethritis.

15. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, for the prevention or treatment of i) diseases resulting from abnormally high plasma or tissue levels of the potent vasoconstrictive peptide endothelin-1 (ET-1), like systemic and pulmonary hypertension, cerebral vasospasm and stroke, asthma, cardiac and renal failure, atherosclerosis, preeclampsia, benign prostatic hyperplasia, and carcinogenesis; ii) a wide range of diseases related to Cathepsin S, including neuropathic hyperalgesia, obesity, and in particular diseases of the immune system, like rheumatoid arthritis (RA), multiple sclerosis (MS), myasthenia gravis, transplant rejection, diabetes, Sj.SLZERO.grens syndrome, Grave's disease, systemic lupus erythematosis, osteoarthritis, psoriasis, idiopathic thrombocytopenic purpura, allergic rhinitis, asthma, atherosclerosis, and chronic obstructive pulmonary disease (COPD); iii) diseases and conditions associated to an overexpression of oxytocin (OT), like preterm delivery; iv) diseases related to a dysfunction in the homoestatic system of the thyrotropin-releasing hormone (TRH), such as infantile spasms, generalized and refractory partial seizures, edematous and destructive forms of acute pancreatrtis, and certain inflammatory disorders (e.g.
autoimmune diseases, inflammatory bowel diseases, cancer-related fatigue or depression, and Alzheimer's disease); v) diseases related to a dysfunction of the bombesin 3 (BB3) receptor, like obesity and impairment of glucose metabolism, disorders of lung development, pulmonary diseases, CNS disorders and carcinogenesis; vi) diseases potentially treatable by blockade of the leukotriene B4 (LTB4) receptor, especially inflammatory and allergic diseases like asthma, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), allergic rhinitis, atopic dermatitis, allergic conjunctivitis, obliterative bronchiolitis after lung transplantation, or interstitial lung diseases;
and/or vii) a wide range of infections caused by microorganisms, in particular strains of Staphylococcus aureus or Streptococcus pneumonia, comprising infections related to: a) respiratory diseases like cystic fibrosis, emphysema, asthma or pneumonia, b) skin or soft tissue diseases such as surgical wounds, traumatic wounds, burn wounds or herpes, smallpox, rubella or measles, c) gastrointestinal diseases including epidemic diarrhea, necrotizing enterocolitis, typhlitis or gastroenteritis or pancreatitis, d) eye diseases such as keratitis and endophthalmitis, e) ear diseases, e.g. otitis, f) CNS
diseases including brain abscess and meningitis or encephalitis, g) bone diseases such as osteochondritis and osteomyelitis, h) cardiovascular diseases like endocartitis and pericarditis, or i) genitourinal diseases such as epididymitis, prostatitis and urethritis.

16. The use of a compound according to any one of claims 1 to 8 for pharmaceutical lead finding.